WO2023161226A1

WO2023161226A1 - Ghrelin agonists with improved potency

Info

Publication number: WO2023161226A1
Application number: PCT/EP2023/054305
Authority: WO
Inventors: Keld Fosgerau; Søren Ljungberg Pedersen
Original assignee: Pephexia Therapeutics Aps
Priority date: 2022-02-22
Filing date: 2023-02-21
Publication date: 2023-08-31

Abstract

The present invention relates to peptides acting as GHSR agonists with improved potency as well as their medical use, in particular in the treatment of cachexia.

Description

Ghrelin agonists with improved potency

FIELD OF THE INVENTION

The present invention relates to peptides acting as GHSR agonists and their use as a medicament, in particular for the treatment of cachexia.

BACKGROUND OF THE INVENTION

Human Ghrelin (hGHR) is an octanoylated peptide hormone with the amino acid sequence GS-S(n- octanoyl)-FLSPEHQRVQQRKESKKPPAKLQPR. hGHR is produced by enteroendocrine cells of the gastrointestinal tract and is primarily secreted from the gut prior to a meal. hGHR is often referred to as "hunger hormone" because it increases food intake and plays an important role in regulating the complex process of energy homeostasis. hGHR adjusts both energy input - by adjusting hunger signals - and energy output - by adjusting the proportion of energy going to ATP production, fat storage, glycogen storage and short-term heat loss. hGHR activates cells in the anterior pituitary gland and hypothalamic arcuate nucleus (ARC) via the gastric vagal afferent nerve and circumventricular organs by triggering the growth hormone secretagogue receptor (GHSR, also known as the ghrelin receptor). These receptors are present in e.g., neuropeptide Y (NPY) and agouti-related protein (AgRP) neurons. Once activated, these neurons produce and release y-aminobutyric acid (GABA) which inhibits anorectic proopiomelanocortin (POMC) neurons, decreasing the release of the anorectic peptide o-melanocyte- stimulating hormone (o-MSH). This effectively reduces the quantity of o-MSH capable of binding to satiety promoting melanocortin 4 receptors (MC4Rs). Concurrently, activated NPY/AgRP neurons increase the production and secretion of the orexigenic (appetite stimulating) peptides NPY and AgRP. NPY is an abundant neuropeptide of the hypothalamus, and one of the most potent orexigenic factors. NPY acts upon the NPY receptors designated NPY1R (Yl), NPY2R (Y2), NPY4R (Y4), and NPY5R (Y5). This receptor family belongs to a class of G protein-coupled receptors (GPCRs) and is expressed in the CNS, especially in regions of the hypothalamus. The receptors NPY1-NPY5 exhibit both anorectic (NPY2, NPY4) and orexigenic effects (NPY5, NPY1) and are activated by the endogenous peptide hormones NPY, PYY and PP. NPY binds to the neuropeptide Y receptor type 1 (NPY1R) and AgRP antagonizes the binding of o-MSH at MC4Rs. The reduction in the anorectic peptide o-MSH and the enhancement of orexigenic peptides NPY and AgRP together reduce the activity of second order anorexigenic neurons in the paraventricular nucleus (PVN), which promotes homeostatic feeding behaviours. Furthermore, the binding of hGHR to GHSR on the pituitary cells also stimulates the secretion of the growth hormone (GH) by the pituitary gland causing an anti-catabolic action on muscle tissue which promotes an increase in muscle mass. Finally, hGHR also stimulates VTA dopamine (DA) neurons increasing the frequency and probability of DA release from their projections in the nucleus accumbens (NA), prefrontal cortex (PFC), hippocampus (HIP), and amygdala (AMY) to encourage mesolimbic reward feeding. Thus, the multiple pharmacological responses orchestrated by hGHR, upon binding to GHSR, makes GHSR a potential target for the treatment of cachexia.

Cachexia is a complex syndrome associated with an underlying illness causing ongoing muscle loss that is only slightly reversed with nutritional supplementation. It is estimated that cachexia affects 6-12 million individuals in Europe, the US, and Japan alone. Cachexia is characterized by an unintended weight loss and muscle strength resulting in an overall lowered quality of life and an increased mortality leading to a total of 1.5-2.0 million deaths per year. A range of diseases may cause cachexia, most commonly cancer, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), chronic kidney disease (CKD) and AIDS. Systemic inflammation from these conditions can cause detrimental changes to metabolism and body composition leading to cachexia. In contrast to weight loss from inadequate caloric intake, cachexia mainly causes muscle loss instead of fat loss. It is estimated that cachexia causes 20-30% deaths of cancer patients globally and that COPD cachexia is associated with an approximately 50% reduction in median survival. Thus, there is a need in the art for effective treatments of cachexia.

Native hGHR, albeit potent, is rapidly cleared with a terminal half-life of approximately 0.2 hours (Eur. J. Endocrinol. (2004), 150, p. 447-455), making it unsuitable for use as a pharmaceutical. hGHR has been shown to undergo desocta noylation in serum by esterases as well as N-terminal proteolysis in liver homogenates. Such desocta noylation has been circumvented in the prior art by substituting the lipidated amino acid Ser(Oct), in position X3 of hGHR, with e.g. Dpr(Oct), as this modification is not subject to deacetylation by esterases (see US 2019/0183966). Previous efforts to extend the half-life of hGHR have been made by various lipidations strategies with fatty acids (see e.g. US 2017/0044230 Al) or conjugation to targeting groups capable of binding Vitamin D Binding protein (see e.g. WO 2013/172967). While such strategies improve the half-life of hGHR, they often result in diminished potency compared to native hGHR. Thus, there is a need in the art for new hGHR analogues with improved potency and/or improved half-life. The present invention relates to the identification of amino acid positions in hGHR that allow for synthesis of new GHSR agonists with improved potency and/or improved half-life. SUMMARY OF THE INVENTION

The present invention relates to peptides acting as ghrelin receptor agonists. In particular, the present invention relates to ghrelin receptor agonists with improved potency. Thus, the present invention relates to the finding that the potency of ghrelin receptor agonists may be improved by introducing certain amino acid substitutions in position X2 and/or Xs. The present invention further relates to the finding that the plasma stability of the new GHSR agonists may be improved, in addition to conventional lipidation strategies, by certain amino acids in position Xu, X12 and/or Xie.

Thus, in a first aspect, the present invention relates to a peptide comprising 28 amino acids (X1-X28) or a pharmaceutically acceptable salt thereof with a relative GHSR EC50 ([GHSR EC50 peptide] / [GHSR ECsoof hGHR]) < 20, wherein the amino acids in position X2 are selected from V, A, or T, and further wherein the peptide has at least 65 % identity to hGHR (SEQ ID NO: 1).

In a second aspect, the present invention relates to a peptide or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of Formula (I),

Xi-X2-Dap-X4-X5-S-P-X₈-H-Xio-Xii-Xi2-Xi3-Xi4-R-Xi₆-E-S-K-K-P-P-A-K-L-X26-P-R

Formula (I) wherein

Xi is P, NMeP, NMeG, G, or absent;

X4 is 1-Nal, F, or Cha;

X₅ is L, I, or V;

X₈ is Y, F, R, K, Cha, T, S, or E;

X10 is Aib, Q, S, or T;

Xu is R or K;

X12 is V, Aib, or NMeV;

X13, X14, and X26 are independently selected as Q, S, or T;

Xie is K, or NMeK; characterized in that X2 is V, A, T; or an analogue thereof having 1, 2 or, 3 substitutions with the proviso that the substitution (s) is/are not present in X2.

In a third aspect, the present invention relates to a peptide or a pharmaceutically acceptable salt thereof according to the first and/or second aspect for use as a medicament. DEFINITIONS AND ABBREVIATIONS

According to the present invention, the peptides are generally amidated (-CONH2) at the C-terminal or non-amidated (-COOH) like the native peptide hGHR. However, the peptides may also comprise another post-translational modification, such as a methyl ester (-COOMe). In a highly preferred embodiment of the invention, the peptides are non-amidated at the C-terminal. In another highly preferred embodiment of the invention, the peptides are amidated at the C-terminal. The peptides according to the present invention may have a free amine (-NH2), be N-acylated (-NHCOR), N-methylated (-NHCH3 or -N(CH3)2) or deaminated at the N-terminal. In a highly preferred embodiment of the invention, the peptides are N-acylated or have a free amine (-NH2) at the N-terminal like the native peptide hGHR.

In the present context, when the disclosure refers to "identity" or "sequence identity" to hGHR (SEQ 1), it should be understood as the number of amino acid residues which match exactly between hGHR and a sequence when aligned. As an example, if a peptide differs in a single position from hGHR when aligned, it has (27 / 28) * 100 = 96.4 % identity to hGHR. Likewise, if it differs in 2 positions from hGHR when aligned, it has (26 / 28) * 100 = 92.9 % identity to hGHR.

According to the present invention, the peptides may be lipidated or non-lipidated depending on the desired half-life. The peptides may e.g., be lipidated at a C-terminal lysine (X29) as exemplified herein.

Lipidation has the usual meaning in the art. Lipidation is typically performed to improve the pharmacokinetic profile of a polypeptide by e.g., improving metabolic stability, reducing enzymatic degradation, lowering excretion and metabolism, resulting in a prolonged in vivo half-life (ti/2). Lipidation may be performed with e.g., fatty acids, sterols, and fat-soluble vitamins, optionally through a linker.

According to the present invention, unless otherwise stated, the amino acids are all L-amino acids (L-stereoisomer, natural amino acids). The abbreviation NMeS refers to the unnatural amino acid N- methyl-L-serine. NMeP refers to the unnatural amino acid N-methyl-L-proline. NMeG refers to the unnatural amino acid N-methyl-L-glycine (sarcosine). NMeV refers to the unnatural amino acid N- methyl-L-valine. NMeK refers to the unnatural amino acid N-methyl-L-lysine. Deg refers to diethylglycine. Tie refers to L-te/t-butyl-glycine. Cha refers to L-cyclohexylalanine. Aib refers to 2-aminoisobutyric acid. 1-Nal refers to 3-(l-naphthyl)-L-alanine. Dpr refers to L-2,3- diaminopropionic acid (3-amino-L-alanine). In the present context, substitutions in an analogue/derivative may be substitutions to natural amino acids as well as unnatural amino acids, including L- and D-stereoisomers. Preferably, a substitution in a variant is a conservative substitution to a conservative amino acid. The groups of conservative amino acids may be defined as:

G, A, V, L, I, P (aliphatic or cyclic)

S, C, T, M (hydroxyl or sulphur containing)

F, Y, W (aromatic)

H, K, R (basic)

D, E, N, Q (acidic or amide)

According to the present invention, the peptides or an analogue/derivative thereof may be in the form of a pharmaceutically acceptable salt. Thus, pharmaceutically acceptable salts are intended to include any salts that are commonly used in formulations of peptides. Such salts include both acid addition salts and basic salts, and examples may be found e.g., in Remington's Pharmaceutical Sciences, 17th edition. Likewise, various solvates of the peptides or an analogue/derivative or a pharmaceutically acceptable salt thereof are also within the scope of the invention.

The person skilled in the art is aware that ECso values depend on the assay type and assay conditions. Thus, in the present context, "a relative GHSR ECso" should be understood as the GHSR ECso value determined for a given peptide divided by the GHSR ECso value determined for hGHR (SEQ ID NO: 1), when measured on the same day using the same cell line, QC criteria, and assay conditions as described herein. As a non-limiting example, the relative GHSR ECso of SEQ ID NO: 28 is calculated as ([GHSR ECso for SEQ ID NO: 28] / [GHSR ECso for hGHR]) = (72.4 / 5.1) = 14.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to peptides acting as ghrelin receptor agonists. In particular, the present invention relates to the finding that the potency (ECso) of ghrelin agonists can be improved by certain amino acid substitutions in position X2 and optionally in position Xs. Furthermore, the present invention relates to the finding that the plasma stability of ghrelin agonists can be improved by certain amino acid substitutions in position Xu, X12, and Xie. High potency is of uttermost importance in drug development for an amount of a drug to produce an effect of given intensity. Highly potent compounds evoke a given response at lower concentrations compared to compounds of lower potency, which ultimately allows for a dose reduction. The invention disclosed herein will be explained by the structure activity relationship (SAR) generated for the peptides SEQ ID NO: 4- 22 in comparison with reference peptide SEQ ID NO: 3, as well as with the SAR generated for the peptides SEQ ID NO: 24-38 in comparison to the reference peptide SEQ ID NO: 23. Furthermore, the invention disclosed herein will be explained by the increased plasma stability shown for SEQ ID NO: 40-43 in comparison with the reference sequence SEQ ID NO: 39. SEQ ID NO: 44-54 illustrates some embodiments of the invention with improved potency and increased plasma stability.

SEQ ID NO: 3 is an analogue of hGHR (SEQ ID NO: 1), wherein the amino acid glutamine (Q) in the positions Xio, X13, Xw and X26 has been substituted with serine (S) in order to prevent deamidation (i.e. assure long-term chemical stability in the formulation of the peptide). Furthermore, the serine (S) in position Xi and the octanoylated amino acid serine (S(Oct)) in X3 of hGHR have been substituted with proline (P) and the octanoylated amino acid Dpr (Dpr(Oct)) respectively, to improve plasma stability (see Fig. 1 below). These modifications cause a reduction in potency (see Formula (II) below, and Table 2). hGHR (SEQ ID NO: 1): GS\ SPEHQRVQQRKESKKPPAKLQPR (EC₅₀ = 3.80 nM)

(SEQ ID NO: 3): PS\ PEHSRVSSRKESKKPPAKLSPR (EC₅₀ = 12.1 nM)

Formula (II)

The peptides SEQ ID NO: 4-22 were designed with a single amino acid substitution in comparison with the reference peptide SEQ ID NO: 3 in order to assess the effect of the substitutions.

SEQ ID NO: 23 is an analogue of SEQ ID NO: 3, wherein the amino acid in position Xs has been substituted with a threonine (T) and wherein a lipidated lysine (K(lipid)) has been introduced in the C-terminal (X29) to improve the half-life (see Formula (III) below).

(SEQ ID NO: 3): PS\_N SPEHSRVSSRKESKKPPAKLSPR

(SEQ ID NO: 23): PS\_N SPTHSRVSSRKESKKPPAKLSPRK

C18DA-VE-OEG-OEG

Formula (III) The introduction of the lipidated lysine in the C-terminal (X29) causes a drop in potency compared to the non-lipidated peptides (see Formula (IV) below, and Table 2).

(SEQ ID NO: 18): PS\_N SPTHSRVSSRKESKKPPAKLSPR (relative EC₅₀ = 1.9)

H

(SEQ ID NO: 23): PS\ A, FLSPTHSRVSSRKESKKPPAKLSPRK (relative EC₅₀ = 16) H S

C18DA-yE-OEG-OEG

Formula (IV)

From SEQ ID NO: 23, each of the peptides SEQ ID NO: 24-38 were designed with a single amino acid substitution in order to assess the effect of the substitutions.

The present invention relates to the realization that sacrifice of potency caused by modifications introduced to optimize other drug parameters, such as chemical stability (e.g. (Q) in the positions Xio, X13, Xw and X26) and/or half-life (e.g., a lipidated lysine in the C-terminal (position X29)), may be (partly) regained by certain amino acids in position X2 by substituting S with the amino acid V, A, or T. It follows that these modifications may also be used in hGHR agonists known in the prior art to improve potency (see e.g., WO 2013/172967).

Amino acids in position X2 for improving potency

The present SAR shows that certain amino acids in position X2 of the hGHR analogues improve the potency. As can be seen, substitution of serine (S in X2) of SEQ ID NO: 23 with NMeS (SEQ ID NO: 25), Tie (SEQ ID NO: 27), Aib (SEQ ID NO: 28), V (SEQ ID NO: 29), T (SEQ ID NO: 30) resulted in improved potency compared to SEQ ID NO: 23 (see Tables 2 and 3). Thus, the inventors found that these amino acids improve the potency of hGHR analogues. Likewise, substitution of serine (S in X2) of SEQ ID NO: 3 with T (SEQ ID NO: 6), A (SEQ ID NO: 7), and V (SEQ ID NO: 8) resulted in improved potency compared to SEQ ID NO: 3 (see Tables 2 and 3). Thus, the amino acids NMeS, Tie, Aib, V, T, and A in X2 were found to result in hGHR analogues with improved potency with the amino acids V, A, and T resulting in the highest potency improvement. Furthermore, the amino acids Tie, Aib, V, and T were found to maintain the excellent in vitro plasma stability of > 58 hours (see Table 2, SEQ ID NO: 27-30). Thus, in an embodiment of the invention, X2 is selected as V, A, T, Tie, Aib, or NMeS. In a preferred embodiment of the invention, X2 is selected as V, A, T, Tie, or Aib. In a more preferred embodiment of the invention, X2 is selected as V, A, T, or Tie. In a highly preferred embodiment of the invention, X2 is selected as V, A, or T. In a yet even more highly preferred embodiment of the invention, X2 is selected as V or A. In the most preferred embodiment of the invention, X2 is V.

Amino acids in position Xi

The examples herein were performed with Xi as proline (P) or absent. Furthermore, from the prior art (see e.g., US 2017/0044230 Al), hGHSR agonists have shown to accommodate NMeG in position Xi besides the native amino acid G. Thus, in an embodiment of the invention, Xi is selected as P, NMeP, NMeG, G, or Xi is absent. In a preferred embodiment of the invention, Xi is selected as P, NMeP, or NMeG. In a more preferred embodiment of the invention, Xi is selected as P or NMeP. In the most preferred embodiment of the invention, Xi is P.

Amino acids in position X4

The examples herein were performed with X4 as F, Cha, or 1-Nal. As can be seen, the SAR shows that the substitution of phenylalanine (F in X4) of SEQ ID NO: 3 with Cha (SEQ ID NO: 9), or 1-Nal (SEQ ID NO: 10) improves the potency. Thus, in an embodiment of the invention, X4 is selected from F, Cha, or 1-Nal. In a preferred embodiment of the invention, X4 is selected from Cha or 1-Nal. In the most preferred embodiment of the invention, X4 is selected from 1-Nal.

Amino acids in position X5

The examples herein were performed with X5 as L, I, or V. Thus, in an embodiment of the invention, X5 is selected as L, I, or V. In a preferred embodiment of the invention, X5 is selected as L or I. In the most preferred embodiment of the invention, X5 is L.

Amino acids in position Xs for improving potency

The examples herein were performed with Xs as Y, F, R, Cha, T, or E. As can be seen from the SAR substitution of glutamic acid (E in Xs) of SEQ ID NO: 3 with the amino acids R (SEQ ID NO: 16), Y (SEQ ID NO: 17), T (SEQ ID NO: 18), F (SEQ ID NO: 19), or Cha (SEQ ID NO: 20) also improves the potency of the peptides. Furthermore, in the prior art (see e.g., WO 2013/113916 A2 and J. Med. Chem. 2017 Sep 14; 60(17): p 7256-7266), hGHR analogues have shown to accommodate S, or K in position Xs. Thus, in an embodiment of the invention, Xs is selected as Y, F, R, K, Cha, T, S, or E. In a preferred embodiment of the invention, Xs is selected as Y, F, R, K, Cha, T, or S. In a more preferred embodiment of the invention, Xs is selected as Y, F, R, K, Cha, orT. In a yet more preferred embodiment of the invention, Xs is selected as Y, F, R, K, or Cha. In an even more preferred embodiment of the invention, Xs is selected as Y, F, R, or K. In a highly preferred embodiment of the invention, Xs is selected as Y, F, or R. In an even more highly preferred embodiment of the invention, Xs is selected as Y or R. In the most preferred embodiment of the invention, Xs is Y.

Amino acids in position Xio

The examples herein were performed with Xio as Aib, Q, S, or T. Thus, in an embodiment of the invention, Xio is selected as Aib, Q, S, or T. In a preferred embodiment of the invention, Xio is selected as Aib, Q, or S. In a more preferred embodiment of the invention, Xio is selected as Aib or Q. In the most preferred embodiment of the invention, Xio is Aib.

Amino acids in position X13, Xu and X26

The examples herein were performed with X13, X14 and X26 as Q or S. Thus, in an embodiment of the invention, X13, Xu and X26 are independently selected from Q, S, or T. In a preferred embodiment of the invention, X13, Xu and X26 are independently selected from Q or S. In the most preferred embodiment, X13, Xu and X26 is Q.

Amino acids in position Xu, X12 and Xiefor improved plasma stability

Albeit the overall good plasma stability of the peptides SEQ ID NO: 23-39 (see Table 2), the inventors identified the plasma metabolites as fragments arising from cleavage between amino acids X11-X12 (cleavage site 2) and between amino acids X15-X16 (cleavage site 1). The inventors found that the plasma stability could be further improved by substitution of the amino acid R in position Xu, the amino acid V X12 (cleavage site 2) and amino acids X15 and Xi6 (cleavage site 1).

SEQ ID NO: 40-43 in comparison with reference SEQ ID NO: 39 show modifications in amino acid position Xu, X12, and X16 resulting in improved plasma stability.

As can be seen from the experimental section "In vitro diluted plasma stability", cleavage at site 1 could be completely prevented by N-methylation of lysine in position X16 (i.e. when X16 is NMeK) or when the amino acids in position X11-X12 was selected as K-Aib. Thus, in a preferred embodiment, X11-X12 is selected as K-Aib. In another preferred embodiment, X16 is selected as NMeK. In a highly preferred embodiment, X11-X12 is selected as K-Aib and X16 is selected as NMeK. As further can be seen, cleavage at site 2 could be completely prevented by simultaneous N-methylation of amino acid position X12 and X16 (i.e. when X12 is NMeV and X16 is NMeK). Thus, in the most preferred embodiment, X12 is selected as NMeV and Xi6 is selected as NMeK. SEQ ID NO: 44-54 was designed with X2 selected as V, A or T to improve potency with simultaneous N-methylation of amino acid position X12 and X16 (i.e. X12 is NMeV and X16 is NMeK) to improve plasma stability.

Thus, in a first aspect, the present invention relates to a peptide comprising 28 amino acids (X1-X28) or a pharmaceutically acceptable salt thereof with a relative GHSR EC50 ([GHSR EC50] I [GHSR EC50 of hGHR]) < 20, wherein the amino acid in position X2 is selected from V, A, orT, and further wherein the peptide has at least 65 % identity to hGHR (SEQ ID NO: 1), most preferably at least 70 % identity to hGHR (SEQ ID NO: 1). In a preferred embodiment of the invention, the relative GHSR EC50 ([GHSR EC50] I [GHSR ECso of hGHR]) < 15. In an even more preferred embodiment of the invention, the relative GHSR EC50 ([GHSR EC50] / [GHSR ECso of hGHR]) < 10. In a highly preferred embodiment of the invention, the relative GHSR EC50 ([GHSR EC50] / [GHSR ECso of hGHR]) < 8. In an even more highly preferred embodiment of the invention, the relative GHSR EC50 ([GHSR EC50] I [GHSR ECso of hGHR]) < 5.

Xi-X₂-Dpr-X₄-X₅-S-P-X₈-H-Xio-Xii-Xi₂-Xi3-Xi4-R-Xi₆-E-S-K-K-P-P-A-K-L-X₂₆-P-R

Formula (I) wherein

Xi is P, NMeP, NMeG, G, or absent;

X₄ is 1-Nal, F, or Cha;

X₅ is L, I, or V;

X₈ is Y, R, F, K, Cha, T, S, or E;

X10 Aib, Q, S, or T;

Xu is R or K;

X12 is V, Aib, or NMeV;

X13, XH, and X26 are independently selected as Q, S, or T;

Xie is K, or NmeK; characterized in that X2 is V, A, or T; or an analogue thereof having 1, 2 or, 3 substitutions with the proviso that the substitution(s) is/are not present in X2.

Preferably, an analogue thereof (i.e. of a peptide of Formula (I)) has 1 or 2 substitutions with the proviso that the substitution (s) is/are not present in X2. More preferably, an analogue thereof (i.e. of a peptide Formula (I)) has 1 substitution with the proviso that the substitution is not present in X2. Most preferably, there is no substitutions (i.e, the invention relates to a peptide of Formula (I))

Formula (I) wherein

Xi is P, NMeP, NMeG, G, or absent;

X₄ is 1-Nal, F, or Cha;

X₅ is L, I, or V;

X₈ is Y, R, F, K, Cha, T, S, or E;

Xio Aib, Q, S, or T;

Xu is R or K;

X12 is V, Aib, or NMeV;

X13, X14, and X26 are independently selected as Q, S, or T;

Xie is K, or NMeK; characterized in that X2 is V, A, or T.

Particularly preferred embodiments

The following section describes preferred embodiments of the second aspect (i.e. embodiments of Formula (I) above) with various combinations of some of the more preferred amino acids in the different positions (i.e. Xi is selected as P, NMeP or NMeG, preferably P; X2 is selected as V, A, T, Tie, or Aib, preferably V, A, or T, more preferably V or A, most preferably V; X₄ is selected as 1-Nal, F, or Cha, preferably 1-Nal; X5 is selected as L, I, or V, preferably L; X₈ is selected as Y, R, F, K, or Cha, preferably Y, F, or R, most preferably Y; Xio is selected as Aib, Q, or S, preferably Aib; Xu is R or K, preferably R; X12 is selected as V, Aib, or NMeV, preferably NMeV; X16 is selected as K, or NMeK, preferably NMeK; X13, Xi₄, X26, are independently selected as Q or S.

In a preferred embodiment Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X₄ is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; X₈ is selected as Y or R or F or K or Cha; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xi₄ is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X₄ is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; X₈ is selected as Y or R or F or K or Cha; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xi₄ is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NmeG; X2 is selected as V or A or T or Tie or Aib; X₄ is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NmeP or NmeG; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1 -Na I or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NmeP or NmeG; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie, or Aib; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1- Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NmeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NmeG; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is selected as 1- Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is selected as 1- Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NmeG; X2 is selected as V or A or T; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xu is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NmeG; X2 is selected as V or A or T; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is 1- Nal; X5 is L; Xs is selected as Y or R or F; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NmeG; X2 is selected as V or A or T; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is 1-Nal; X5 is L; Xs is Y; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A or T; X4 is 1-Nal; X5 is L; Xs is Y; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NmeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; Xie is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NmeG; X2 is selected as V or A; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; Xi6 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NmeG; X2 is selected as V or A; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; Xie is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is 1-Nal; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V or A; X4 is 1-Nal; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NmeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xu is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xu is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or F or R; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xu is selected as Q or S; Xu is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X is selected as Q or S; Xu is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xu is selected as Q or S; Xu is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xu is selected as Q or S; Xu is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xu is selected as Q or S; Xu is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xu is selected as Q or S; Xu is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xu is selected as Q or S; Xu is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xu is selected as Q or S; Xu is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NmeG; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xu is selected as Q or S; Xi6 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; Xie is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is selected as P or NMeP or NMeG; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; Xie is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; Xi6 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; Xi4 is selected as Q or S; Xi6 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T or Tie or Aib; X4 is 1-Nal; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; Xie is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1- Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; Xie is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is 1- Nal; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A orT; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is 1- Nal; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is 1-Nal; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A or T; X4 is 1-Nal; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1- Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1-Nal; Xs is selected as L or I or V; Xs is Y; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1- Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; Xie is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1-Nal; X5 is L; Xs is Y; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V or A; X4 is 1-Nal; X5 is L; Xs is Y; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; Xio is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is selected as Y or R or F; Xio is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; Xi6 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is selected as 1-Nal or F or Cha; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; Xie is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is selected as L or I or V; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F or K or Cha; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is selected as Y or R or F; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is Y; X10 is selected as Aib or Q or S; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S. In another preferred embodiment, Xi is P; X2 is selected as V; X4 is 1-Nal; X5 is L; Xs is Y; X10 is Aib; Xu is selected as R or K; X12 is selected as V, Aib, or NMeV; X13 is selected as Q or S; X14 is selected as Q or S; X16 is selected as K, or NMeK; X26 is selected as Q or S.

In any of the particularly preferred embodiments mentioned above, it should be understood that most preferably, Xu is R; X12 is NMeV; and X16 is NMeK.

Medical use

In a third aspect, the present invention relates to a peptide or a pharmaceutically acceptable salt thereof according to the first and/or second aspect for use as a medicament. In the most preferred embodiment of aspect three, the peptides or a pharmaceutically acceptable salt thereof are for use in the treatment of cachexia. The preferred embodiments described for aspect one or two apply equally for aspect three. Lipidation

In any of the above-mentioned aspects or embodiments, the amino acid Dpr in position X3 is preferably lipidated with a saturated or unsaturated C6-C12 fatty acid. Preferably, the fatty acid is selected from the group consisting of octanoic acid (octanoyl), nonanoic acid (nonanoyl), or decanoic acid (decanoyl). Most preferably, the fatty acid is octanoic acid (octanoyl) as in hGHR. Furthermore, the peptides may comprise a further lipidation (besides Dpr in position X3) in order to obtain the desired PK profile of the peptide. Various lipidation strategies are well known in the prior art. hGHR analogues lipidation strategies in the prior art have shown or suggested that lipidation may be performed by introduction of lysine residues in position Xs, X10, Xu, X13, X14, X16, X19, X20, X24, X26 and X28 (see e.g., WO 2013/113916). The present inventors have further found that the hGHSR agonists according to the invention can be lipidated in the C-terminal by introducing the amino acid lysine (K) in X29. Thus, lipidation (if present) is preferably performed in one of the positions Xs, X10, Xu, X13, X14, Xie, X19, X20, X24, X26, X280r X29, most preferably in position X29 by introducing a lysine residue (i.e., K). Most preferably, the lipid is a C18DA or C20DA connected to the lysine (K) residue via the linker -yE-OEG-OEG- (i.e., K(C18DA-yE-OEG-OEG-) or K(C20DA-yE-OEG-OEG-) as exemplified herein).

EXAMPLES

Synthesis

Peptides were synthesized using standard Fmoc (fluorenylmethyloxycarbonyl) chemistry using Rink Amide HMBA Resin (0.30 mmol, 1.00 eq, loading 0.28 mmol/g). Fmoc removal was performed using 20% piperidine in dimethylformamide (DMF) (10 mL) and agitated with nitrogen for 15 min. The resin was washed with dimethylformamide (DMF) five times (10 mL) and filtered. The consecutive amino acid couplings were performed using a solution of 2-(lH-benzotriazole-l-yl)-l, 1,3,3- tetramethyluronium hexafluorophosphate (HBTU) (2.85 eq), N,N-diisopropylethylamine (DIPEA) (6 eq) and Fmoc-protected amino acids (3 eq) in dimethylformamide (DMF) (5 mL) and agitated with nitrogen bubbling for 30 min at 20°C. The resin was then washed five times with dimethylformamide (DMF) (10 mL). The Fmoc-protected amino acids building blocks used were the standard recommended: Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Cys(tBu)-OH, Fmoc-Met-OH, Fmoc- Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc- His(Trt)-OH, Fmoc-Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Lys(Dde)-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Val-OH, Fmoc-NMeSer(tBu)-OH, Fmoc-Deg-OH, Fmoc-L-Tle-OH, Fmoc-Aib-OH, Fmoc-lNal- OH, Boc-Pro-OH, Boc-Gly-OH, NMePro-OH, Fmoc-L-Dpr(octanoyl)-OH, Boc-NMeGly-OH, Fmoc-OEG- OH, Fmoc-Glu-OtBu, and Octadecanedioic acid mono-tert-butyl ester. If nothing else is specified, the natural L-form of the amino acids was used. Fmoc removal and coupling steps were repeated until the desired peptide sequence was achieved. The resultant linear peptide was used directly in the next step. To remove the Dde protecting group, 3% N2H H2O in DMF was added and the reaction was reacted for 30 min, drained, and the deprotection was repeated. Elongation at the sidechain of the deprotected Lys as described for the standard couplings and Fmoc-deprotection but using 2- (lH-7-Azabenzotriazol-l-yl)-l,l,3,3-tetramethyluronoium hexafluorphosphate (HATU) as coupling reagent instead of HBTU.

Peptide cleavage and purification

The resin was washed with methanol (20 mL x 5) and dried under vacuum to get peptide resin. Subsequently, the peptidyl resin was then treated with the cleavage cocktail (92.5% TFA (trifluoroacetic acid)/ 2.5% triisopropyl silane (TIPS) / 2.5% 3-mercaptopropionic acid (Mpr) / 2.5% H2O) (15 mL) for 150 min and the peptide TFA mixture was collected. The peptide was precipitated with cold isopropyl ether and centrifuged (2 min at 3000 rpm). The peptide precipitation was washed with isopropyl ether for two more times. The crude peptide was dried over vacuum for 2 hours. The peptide was re-dissolved in an acetonitrile/ water mixture and purified by preparative HPLC, and the target peptide fractions was freeze-dried to give a white solid.

Preparative HPLC purification method:

System: Gilson GX-281

Column: Gemini, 5 pm, C18, 110 A followed by a Luna, C18, 10 pm, 100 A.

Gradient: 21-41% 0-50 min.

Flow rate: 20 mL/min

Diode array: 214/254 nm

Column temperature: 30°C

Solvent A: 0.075% TFA in water

Solvent B: Acetonitrile

HPLC QC method:

System: Agilent Infinity II 1260 HPLC series

Column: Gemini C18, llOA, 5 pm, 150 x 4.6mm

Gradient: Gradient run-time 20 minutes; 0.00-20.00 min 15-45% B. Column cleaning and equilibration; 20.00-20.10 45-95% B, 20.10-23.00 min 95% B, 23.00-23.10 min 95-15% B, 23.10-28.00 min 15% B

Flow rate: 1.0 mL/min

Diode array: 220/254 nm

Column temperature: 30°C Solvent A: 0.1% TFA in water

Solvent B: 0.075% TFA in acetonitrile

LC-MS method for final products:

System: Agilent Infinity II 1260 HPLC series

Column: Xbridge C18, 130A, 3.5 pm, 2.1 x 30mm

Detector: Agilent LCMS (G6125C), single quadrupole TIC scan

Scanning range: m/z min 100, m/z max. 2000, positive mode

Gradient: Gradient run-time 1 minutes; 0.00-1.00 min 10-80% B. Column cleaning and equilibration; 1.00-1.01 80-95% B, 1.01-1.60 min 95% B, 1.60-1.61 min 95-10% B, 1.61-2.00 min 10% B

Flow rate: 1.2 mL/min

Diode array: 220/254 nm

Column temperature: Room temperature

Solvent A: 0.1% TFA in water

Solvent B: 0.075% TFA in acetonitrile

The peptides without a lipidation in the C-terminal were synthesized by the USPS LIPS technology (from Peptides&Elephants) with an average crude purity of 70%. The whole synthesis process was highly automated using custom-made synthesis robots. Each amino acid or building block was delivered by its individual pipette, thus excluding cross-contamination. The coupling and deprotection reagents were like in the standard method described above. The peptides were cleaved from the solid support, washed by precipitation, and subsequently freeze-dried. The peptides were characterized by LC-MS and tested in the Ghrelin assay in crude form.

The functional assay

The in vitro functional measurements were all performed by EuroScreen Fast, a CRO unit of Epics Therapeutics S.A., in Gosselies, Belgium. The peptides were tested towards hGHSR using IPOne HTRF functional assays. The receptor accession numbers, cellular background and reference compounds were GHSR NP_940799.1 CHO-Kl-mt aequorin Human Ghrelin. On each day of experimentation, reference compounds were tested at several concentrations in technical duplicate (n=2) to obtain a dose-response curve and an estimated EC50 value. Reference values thus obtained for the test were compared to historical values obtained from the same receptor and used to validate the experimental session. For replicate determinations, the maximum variability tolerated in the test was of +/-20% around the average of the replicates. Dose-response data from test compounds were analysed with XLfit (IDBS) software using nonlinear regression applied to a sigmoidal dose-response model and the following equation: XL Fit Model 203: 4 Parameter Logistic Model

A: Bottom B: TOP

C: LogECso 20 D: Hill fit= (A+((B-A)/(l+(((10 C)/x) D)))) inv= ((10^AC)/((((B-A)/(y-A))-l)^A(l/D))) res = (y-fit)

In vitro concentrated plasma stability

Stocks of each of test peptides (SEQ ID NO: 2 and 23-38) in 1 mM were prepared. Moreover, Somatostatin acetate (control) and Propantheline bromide (control) were prepared in 10 mM. The test peptides and control were diluted into working solution: 20 pL of test peptide and control (except Propantheline bromide) stock solution (1 mM in dimethyl sulfoxide (DMSO)) were diluted with 180 pL of DMSO (Working solution concentration: 100 pM, 100% DMSO). Propantheline bromide was diluted into working solution: 5 pL of Propantheline bromide stock solution (10 mM in H2O) were diluted with 495 pL of H2O (working solution concentration: 100 pM, 100% H2O). Pooled frozen plasma was thawed in a water bath at 37°C prior to experiment. Plasma was centrifuged at 4000 rpm for 5 min., and the clots were removed, if any. Using an Apricot automation workstation, 98 pL/well of blank plasma were added to all 96-well reaction plates. (Blank, TO, T2, T4, T8 and T24 hrs). An Apricot automation workstation was used to add 2 pL/well of working solution (100 pM) to all reaction plates except Blank. (TO, T2, T4, T8 and T24 hrs). All reaction plates containing mixtures of compound and plasma were incubated at 37°C in water bath. The reaction plates were incubated at 37°C, and the timer was started. At the end of incubation, 100 pL 4% H3PO4 was mixed with 100 pL spiked plasma samples, then 800 pL of stop solution was added (200 ng/mL tolbutamide and 200 ng/mL labetalol in MeOH) to precipitate protein and mixed thoroughly. Each plate was sealed and shaken for 20 minutes. After shaking, each plate was centrifuged at 4000 rpm and 4°C for 20 minutes. After centrifugation, an Apricot automation workstation was used to transfer 150 pL of supernatant from each reaction plate to its corresponding bioanalysis plate. Each bioanalysis plate was sealed and shaken for 10 minutes prior to LC-MS/MS analysis. The % remaining of test compound after incubation in plasma was calculated using following equation: % Remaining= 100 x (PAR at appointed incubation time / PAR at TO time), where PAR is the peak area ratio of analyte versus internal standard (IS). The appointed incubation time points were TO (0 min), Tn (n=0, 2, 4, 8, 24 hrs). In this assay, the peptide to albumin ratio was approximately 1:1700, and most of the peptide will be stabilized by binding to albumin. Results are shown in Table 2.

In vitro diluted plasma stability

Each of the following peptides were solubilized in distilled water at concentration of 1 mg/mL; SEQ

ID NO 39, 42, and 43. Subsequently, 8% v/v of plasma was added to each peptide solution. The solutions were incubated at 37 °C for 60, 120 and 180 minutes. After incubation, the solutions were precipitated with acetonitrile in proportion 1:1 and centrifuged at 14000 rpm for 15 min at 4 °C. The supernatants were analysed by LC/MS (ESI) (Agilent 6410 Triple Quadrupole LC/MS). Percent remaining of test compound was calculated as: 100 x (AUC(parent ion) at appointed incubation time I AUC(parent ion) at time 0). Mobile phase A was 10% acetonitrile, 0.1 % formic acid in ultrapure water, while mobile phase B was 0.1 % formic acid in acetonitrile. The gradient was set for 15 minutes 30-40% B. 3 uL of solution was injected at a flow rate of 0.4 mL/min and detected at 214 nm. A Kinetex 2.6 pm C8 100 A; 150 x 4.6 mm LC column was used. The mass range was 200-2000 m/z, positive voltage. In this assay, the peptide to albumin ratio is approximately 4:1 and most of the peptide will be in solution and accessible to plasma proteases.

SEQ ID NO 39 had an in vitro half-life of 0.93 hrs and showed to have degradation between Argil and Vall2 as well as between Argl5 and Lysl6. In comparison, SEQ ID NO 40 and 41 having a single N-methylation have an in vitro half-life of 1.33 and 1.26 hrs, respectively. SEQ ID NO 42 having two N-methylations showed to be fully stabilized at the two positions and has an in vitro halflife of 1.78 hrs. Thus, in a preferred embodiment, X12 is NMeV, or X16 is NMeK to further improve the plasma stability of the peptides. In a most preferred embodiment, X12 is NMeV, and Xi6 is NMeK to further improve the plasma stability of the peptides. Likewise, SEQ ID NO 43 showed to have an in vitro half-life of 1.78 hrs and no cleavage at the two identified cleavage sites. Thus, in a preferred embodiment, Xu is K; X12 is Aib; and X16 is NMeK to further improve the plasma stability of the peptides. Also, the N-methylation of Vall2 in combination with N-methylation of Lysl6 only had little effect on the hGHR. potency (2-4 fold).

Claims

1. A peptide or a pharmaceutically acceptable salt thereof comprising the amino acid sequence of Formula (I),

Formula (I) wherein

Xi is P, NMeP, NMeG, G, or absent;

X₄ is 1-Nal, F, or Cha;

X₅ is L, I, or V;

X₈ is Y, R, F, K, Cha, T, S, or E;

Xio Aib, Q, S, or T;

Xu is R or K;

X12 is V, Aib, or NMeV;

X13, X14, and X26 are independently selected as Q, S, or T;

Xie is K, or NMeK; characterized in that X2 is V, A, or T; or an analogue thereof having one substitution with the proviso that the substitution is not present in X2.

2. A peptide or a pharmaceutically acceptable salt thereof according to claim 1, wherein X2 is V or A.

3. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein X2 is V.

4. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein X₈ is Y, R, F, K, or Cha.

5. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein X₈ is Y, R, or F.

6. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein X₄ is Cha or 1-Nal.

7. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein Xio is Aib, Q, or S.

8. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein Xio is Aib, or Q.

9. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein Xi6 is NMeK.

10. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein X11-X12 is K-Aib.

11. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein Xu is R; X12 is NMeV; and X16 is NMeK.

12. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein X13, X14, and X26 are independently selected as S or Q.

13. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein X5 is L or I.

14. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein Xi is P, NMeP, or NMeG.

15. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein Dpr in position X3 is lipidated with octanoic acid (Dpr-octanoyl), nonanoic acid (Dpr-nonanoyl), or decanoic acid (Dpr-decanoyl).

16. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, wherein the peptide comprises a lysine (K) in position X29 that is lipidated, optionally through a linker.

17. A peptide or a pharmaceutically acceptable salt thereof according to any of the preceding claims, for use as a medicament.