WO2005032494A2 - Lpa receptor agonists and antagonists and methods of use - Google Patents
Lpa receptor agonists and antagonists and methods of use Download PDFInfo
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- WO2005032494A2 WO2005032494A2 PCT/US2004/033601 US2004033601W WO2005032494A2 WO 2005032494 A2 WO2005032494 A2 WO 2005032494A2 US 2004033601 W US2004033601 W US 2004033601W WO 2005032494 A2 WO2005032494 A2 WO 2005032494A2
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- C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C233/02—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals
- C07C233/04—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
- C07C233/05—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having nitrogen atoms of carboxamide groups bound to hydrogen atoms or to carbon atoms of unsubstituted hydrocarbon radicals with carbon atoms of carboxamide groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/08—Esters of oxyacids of phosphorus
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- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
- C07F9/165—Esters of thiophosphoric acids
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- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
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- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/06—Phosphorus compounds without P—C bonds
- C07F9/16—Esters of thiophosphoric acids or thiophosphorous acids
- C07F9/165—Esters of thiophosphoric acids
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- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
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- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/40—Esters thereof
- C07F9/4003—Esters thereof the acid moiety containing a substituent or a structure which is considered as characteristic
- C07F9/4006—Esters of acyclic acids which can have further substituents on alkyl
Definitions
- LPA/LPA receptor involvement in a number of cellular pathways and cell activities such as proliferation and/or migration, as well as their implication in wound healing and cancer, it would be desirable to identify novel compounds which are capable of acting, preferably selectively, as either antagonists or agonists at the LPA receptors identified above.
- LPA receptor inhibitors There are cunently very few synthetic or endogenous LPA receptor inhibitors which are known. Ofthe antagonists reported to date, the most work was done on SPH, SPP, N-palmitoyl-1-serine (Bittman et al., 1996), and N-palmitoyl-1- tyrosine (Bittman et al., 1996). It is known that the above-mentioned compounds inhibit LPA-induced chloride cunents in the Xenopus oocyte (Bittman et al., 1996;
- R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently hydrogen, a straight or branched-chain CI to C30 alkyl, a straight or branched-chain C2 to C30 alkenyl, an aromatic or heteroaromatic ring with or without mono-, di-, or tri- substitutions ofthe ring, an acyl including a CI to C30 alkyl or aromatic or heteroaromatic ring, an arylalkyl including straight or branched-chain CI to C30 alkyl, or an aryloxyalkyl including straight or branched-chain CI to C30 alkyl.
- Q 1 NR 4 ;
- Q 2 is H 2 ;
- X 1 and X 2 are linked together as — O— PO(OH)— O— ;
- X 3 is R 1 — Y 1 — A— , with A being a direct link and Y 1 being — NH — •.
- R 1 and R 4 are as defined above for formula (I).
- Q 1 and Q 2 are both H 2 ; one of X 1 and X 2 is (HO) 2 PS— Z 1 — , with Z 1 being O; and one of X 1 , X 2 , and X 3 is R 1 — Y 1 — A — , with A being a direct link and Y 1 being — CH 2 — .
- R 1 is as defined above for formula (I).
- Prefened R 1 groups are saturated and unsaturated C2 to C20 hydrocarbons, both straight and branched chain; most prefened R 1 groups are saturated and unsaturated C4 to C12 hydrocarbons.
- the synthesis of difluorothiophosphonates according to formula (VIII) is outlined in scheme 3 of Figure 1.
- the tefradecyl difluorophosphonate analog was synthesized (scheme 3) in two steps using diethyl difluoromethanephosphonate as the starting material (Halazy et al., 1991).
- the non-cyclic compounds ofthe present invention can be prepared by reacting (Y 2 O) 2 PO— Z 11 — Z 13 , (Y 2 O) 2 PO— Z 12 — P(OH)S— Z 11 — Z 13 , where Z 11 is — (CH 2 ), declarat— , — CF 2 — , — CF 2 (CH 2 ) classroom— , or — O(CH 2 ) m — with m being an integer from 1 to 50, — C(R 3 )H— , or — O— , Z 12 is — (CH 2 ) deliberately— or — O(CH 2 ) theory— with n being an integer from 1 to 50 or — O — , Z 13 is H or a first leaving group or — Z 1 x — Z 13 together to form the first leaving group, and Y 2 is H or a protecting group; with an intermediate compound according to formula (IX) in the presence of sulfur, followed by a de-protection step, if necessary,
- R 11 for each of X 11 , X 12 , or X 13 , is independently hydrogen, a straight or branched-chain CI to C30 alkyl, a straight or branched-chain C2 to C30 alkenyl, an aromatic or heteroaromatic ring with or without mono-, di-, or tri- substitutions ofthe ring, an acyl including a CI to C30 alkyl or an aromatic or heteroaromatic ring, an arylalkyl including straight or branched-chain CI to C30 alkyl, an aryloxyalkyl including straight or branched-chain CI to C30 alkyl,
- R 12 , R 13 , R 14 , R 15 , R 16 , and R 17 are independently hydrogen, a sfraight or branched-chain CI to C30 alkyl, a straight or branched-chain C2 to C30 alkenyl, an aromatic or heteroaromatic ring with or without mono-, di-, or tri-substitutions ofthe ring, an acyl including a CI to C30 alkyl or aromatic or heteroaromatic ring, an arylalkyl including straight or branched-chain CI to C30 alkyl, or an aryloxyalkyl including straight or branched-chain CI to C30 alkyl.
- a further aspect ofthe present invention relates to a pharmaceutical composition that includes a pha ⁇ naceutically-acceptable carrier and a compound ofthe present invention.
- the pharmaceutical composition can also include suitable excipients, or stabilizers, and can be in solid or liquid form such as, tablets, capsules, powders, solutions, suspensions, or emulsions.
- the composition will contain from about 0.01 to 99 percent, preferably from about 20 to 75 percent of active compound(s), together with the carrier, excipient, stabilizer, etc.
- the solid unit dosage forms can be ofthe conventional type.
- the compounds ofthe present invention in solution or suspension may be packaged in a pressurized aerosol container together with suitable propellants, for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
- suitable propellants for example, hydrocarbon propellants like propane, butane, or isobutane with conventional adjuvants.
- the materials ofthe present invention also may be administered in a non-pressurized form such as in a nebulizer or atomizer.
- Typical dosages comprise about 0.01 to about 100 mg/kg-body wt.
- the prefened dosages comprise about 0.1 to about 100 mg/kg-body wt.
- the most prefened dosages comprise about 1 to about 100 mg/kg-body wt.
- Treatment regimen for the administration ofthe compounds ofthe present invention can also be determined readily by those with ordinary skill in art. Certain compounds ofthe present invention have been found to be useful as agonists of LPA receptors while other compounds ofthe present invention have been found useful as antagonists of LPA receptors. Due to their differences in activity, the various compounds find different uses.
- the prefened animal subject of the present invention is a mammal, i.e., an individual belonging to the class Mammalia. The invention is particularly useful in the treatment of human subjects.
- One aspect ofthe present invention relates to a method of modulating
- EDG-4 LPA
- Genbank Accession No. NM_004720 Genbank Accession No. NM_004720
- An EDG-4 encoding nucleic acid molecule has a nucleotide sequence according to SEQ. ID. No. 3 as follows:
- the encoded EDG-4 (LPA 2 ) receptor has an amino acid sequence according to SEQ. ID. No. 4 as follows:
- EDG-7 LPA 3
- An EDG-7 encoding nucleic acid molecule has a nucleotide sequence according to SEQ. ID. No.
- the encoded EDG-7 (LPA 3 ) receptor has an amino acid sequence according to SEQ. ID. No. 6 as follows:
- a PSP-24 encoding nucleic acid molecule has a nucleotide sequence according to SEQ. ID. No. 7 as follows:
- the encoded PSP-24 receptor has an amino acid sequence according to SEQ. ID. No. 8 as follows:
- VNSTAVPTTP AAFKSLNLPL QITLSAIMIF ILFVSFLGNL VVCL VYQKA AMRSAINILL 120
- LPA receptor agonists will characteristically induce LP A-like activity from an LPA receptor, which can be measured either chemically, e.g., Ca 2+ or CI " current in oocytes, or by examining changes in cell morphology, mobility, proliferation, etc.
- LPA receptor antagonists will characteristically block LP A-like activity from an LPA receptor. This too can be measured either chemically, e.g., Ca 2+ or CT cunent in oocytes, or by examining changes in cell morphology, mobility, proliferation, etc.
- the present invention also relates to a method of inhibiting LPA- induced activity on an LPA receptor.
- This method includes providing a compound of the present invention which has activity as an LPA receptor antagonist and contacting an LPA receptor with the compound under conditions effective to inhibit LPA-induced activity ofthe LPA receptor.
- the LPA recepter can be as defined above.
- the LPA receptor is present on a cell which normally expresses the receptor or which heterologously expresses the receptor.
- the contacting ofthe LPA receptor with the compound ofthe present invention can be performed either in vitro or in vivo.
- LPA is a signaling molecule involved in a number of different cellular pathways which involve signaling through LPA receptors, including those LPA receptors described above. Therefore, it is expected that the compounds of the present invention will modulate the effects of LPA on cellular behavior, either by acting as LPA receptor antagonists or LPA receptor agonists.
- One aspect ofthe present invention relates to a method of treating cancer which includes providing a compound ofthe present invention and administering an effective amount ofthe compound to a patient in a manner effective to treat cancer.
- the types of cancer which can be treated with the compounds ofthe present invention includes those cancers characterized by cancer cells whose behavior is attributable at least in part to LPA-mediated activity. Typically, these types of 2005/032494 29 .
- cancer are characterized by cancer cells which express one or more types of LPA receptors.
- Exemplary forms of cancer include, without limitation, prostate cancer, ovarian cancer, and bladder cancer.
- the compounds ofthe present invention which are particularly useful for cancer treatment are the LPA receptor antagonists.
- administering the compounds ofthe present invention they can be administered systemically or, alternatively, they can be administered directly to a specific site where cancer cells are present. Thus, administering can be accomplished in any manner effective for delivering the compound to cancer cells.
- the LPA receptor antagonists upon binding to LPA receptors, will inhibit proliferation or metastasis ofthe cancer cells or otherwise destroy those cancer cells.
- LPA antagonist compounds ofthe present invention were cytotoxic to prostate cancer cell lines which express one or more LPA receptors ofthe type described above.
- the pharmaceutical composition can also contain, or can be administered in conjunction with, other therapeutic agents or treatment regimen presently known or hereafter developed for the treatment of various types of cancer.
- Cancer invasion is a complex multistep process in which individual cells or cell clusters detach from the primary tumor and reach the systemic circulation or the lymphatics to spread to different organs (Liotta et al., 1987).
- tumor cells must anest in capillaries, exfravasate, and migrate into the sfroma ofthe tissue to make secondary foci.
- tumor cells must recognize signals on the endothelial cell that arrest them from the circulation.
- tumor cells must attach to the basement membrane glycoprotein laminin via the cell surface laminin receptors.
- tumor cells secrete proteases to degrade the basement membrane.
- the third step of invasion is tumor cell migration.
- Cell motility plays a central role in tumor cell invasion and metastasis. The relationship between motility of tumor cells in vitro and the metastatic behavior in animal experiments indicates a strong direct conelation (Hoffman-Wellenhof et al., 1995).
- LNCaP lines showed that EDG-2, 4, 5, and EDG-7 are present in all three prostate cancer cell lines, whereas EDG-3 is present in LNCaP and DU-145 prostate cancer cell lines.
- Another aspect ofthe present invention relates to a method of enhancing cell proliferation.
- This method of enhancing cell proliferation includes the steps of providing a compound ofthe present invention which has activity as an agonist of an LPA receptor and contacting the LPA receptor on a cell with the compound in a manner effective to enhance LPA receptor-induced proliferation ofthe cell.
- LPA plays in modulating cancer cell activity, there is strong evidence to suggest that LPA also has a physiological role in natural wound healing.
- LPA derived from activated platelets is believed to be responsible, at least in part, for stimulating cell proliferation at the site of injury and inflammation possibly in synchronization with other platelet-derived factors (Balazs et al., 2000).
- LPA by itself stimulates platelet aggregation, which may in turn be the factor that initiates an element of positive feedback to the initial aggregatory response (Schumacher et al., 1979; Tokumura et al., 1981; Genard et al., 1979; Simon et al., 1982).
- compounds having LPA receptor agonist activity can be used in a manner effective to promote wound healing.
- another aspect ofthe present invention relates to a method of treating a wound.
- This method is carried out by providing a compound ofthe present invention which has activity as an agonist of an LPA receptor and delivering an effective amount ofthe compound to a wound site, where the compound binds to LPA receptors on cells that promote healing ofthe wound, thereby stimulating LPA receptor agonist-induced cell proliferation to promote wound healing.
- the primary goal in the treatment of wounds is to achieve wound closure.
- Open cutaneous wounds represent one major category of wounds and include burn wounds, neuropathic ulcers, pressure sores, venous stasis ulcers, and diabetic ulcers.
- Open cutaneous wounds routinely heal by a process which comprises six major components: i) inflammation, ii) fibroblast proliferation, iii) blood vessel proliferation, iv) connective tissue synthesis v) epithelialization, and vi) wound contraction. Wound healing is impaired when these components, either individually or as a whole, do not function properly. Numerous factors can affect wound healing, including malnutrition, infection, phannacological agents (e.g., actinomycin and steroids), diabetes, and advanced age (see Hunt and Goodson, 1988). Phospholipids have been demonstrated to be important regulators of cell activity, including mitogenesis (Xu et al., 1995b), apoptosis, cell adhesion, and regulation of gene expression.
- LPA elicits growth factorlike effects on cell proliferation (Moolenaar, 1996) and cell migration (Imamura et al., 1993). It has also been suggested that LPA plays a role in wound healing and regeneration (Tigyi and Miledi, 1992). In general, agents which promote a more rapid influx of fibroblasts, endothelial and epithelial cells into wounds should increase the rate at which wounds heal.
- Compounds of the present invention that are useful in treating wound healing can be identified and tested in a number of in vitro and in vivo models.
- tissue culture cells such as fibroblasts (Verrier et al., 1986), endothelial cells (Miyata et al., 1990) or epithelial cells (Kartha et al., 1992).
- Other systems permit the measurement of endothelial cell migration and/or proliferation (Muller et al., 1987; Sato et al., 1988).
- wound healing In vivo models for wound healing are also well-known in the art, including wounded pig epidermis (Ohkawara et al., 1977) or drug-induced oral mucosal lesions in the hamster cheek pouch (Cherrick et al., 1974).
- the compounds ofthe present invention which are effective in wound healing can also be administered in combination, i.e., in the pharmaceutical composition ofthe present invention or simultaneously administered via different routes, with a medicament selected from the group consisting of an antibacterial agent, an antiviral agent, an antifungal agent, an antiparasitic agent, an antiinflammatory agent, an analgesic agent, an antipruritic agent, or a combination thereof.
- a prefened mode of administration is by the topical route.
- the agent may be administered by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal or transdermal routes.
- administration may be by the oral route.
- the dosage administered will be dependent upon the age, health, and weight ofthe recipient, kind of concunent treatment, if any, frequency of treatment, and the nature ofthe effect desired.
- it is prefened to administer an effective amount of a compound according to the present invention to the wounded area, e.g., skin surfaces.
- a prefened topical preparation is an ointment wherein about 0.01 to about 50 mg of active ingredient is used per ml of ointment base, such as PEG- 1000.
- the present invention further provides methods of inhibiting apoptosis or preserving or restoring cell, tissue or organ function. This method is carried out by providing a compound ofthe present invention which has activity as an agonist of an LPA receptor and contacting a cell, tissue, or organ with an amount ofthe compound which is effective to treat apoptosis, or preserve or restore function in the cell, tissue, or organ.
- the treatment can also diminish the apoptosis-related problems associated with immunosuppressing viruses, chemotherapeutic agents, radiation, and immunosuppressive drugs. These stimuli trigger apoptosis in a variety of disorders, including, but not limited to, those of the digestive tract tissues and associated gastrointestinal perturbations.
- a prefened compound for practicing this aspect ofthe present invention is compound 8g, particularly with respect to the protection of gastroendothelial cells against chemotherapeutic- or radiation-induced apoptosis as described in the Examples herein.
- the treatments are also suitable during all phases of organ transplantation.
- the compounds having agonist activity on an LPA receptor can be used to prepare the organ by administering an amount ofthe compound to the donor effective to stabilize or preserve the organ.
- the organ can be perfused and/or preserved in OPS containing the compound.
- the organ recipient can then be administered an amount ofthe compound effective to enhance organ stability and function.
- the compositions are also particularly suitable for use in treating cardioplegia, whether related to transplantation or other surgical intervention.
- Gastrointestinal perturbations include, but are not limited to, damage to the lining ofthe gut, severe chronic ulcers, colitis, radiation induced damage, chemotherapy induced damage, and the perturbation ofthe gastrointestinal tract caused by parasites, and diarrhea from any other cause.
- Various viral and bacterial infections are known to result in gastrointestinal perturbations.
- the compounds having agonist activity on an LPA receptor are also suitable for use in treatment ofthe side effects associated with these infections. Such compounds are particularly suited for use in ameliorating the gastrointestinal disturbances associated with chemotherapy.
- Such compounds are suitable for use not only in preventing the dianhea associated with chemotherapy but also the nausea.
- These compounds are particularly suited to treatment of various gastrointestinal conditions in animals, including, but not limited to livestock and domesticated animals. Such conditions, particularly dianhea, account for the loss of many calves and puppies to dehydration and malnutrition.
- Treatment of gastrointestinal conditions is preferably by gastrointestinal administration. In the case of cattle and domesticated animals, an effective amount of these compounds can be conveniently mixed in with the feed.
- administration can be by any method known in the art of gastrointestinal administration.
- administration is oral.
- the compounds having agonist activity on an LPA receptor can be administered to immunodeficient patients, particularly HIV-positive patients, to prevent or at least mitigate apoptotic death of T cells associated with the condition, which results in the exacerbation of immunodeficiencies as seen in patients with AIDS.
- administration to such patients is parenterally, but can also be transdermally or gastrointestinally.
- the compounds having agonist activity on an LPA receptor can also be administered to treat apoptosis associated with reperfusion damage involved in a variety of conditions, including, but not limited to, coronary artery obstruction; cerebral infarction; spinal/head trauma and concomitant severe paralysis; reperfusion damage due to other insults such as frostbite, coronary angioplasty, blood vessel attachment, limb attachment, organ attachment and kidney reperfusion.
- Myocardial and cerebral infarctions (stroke) are caused generally by a sudden insufficiency of arterial or venous blood supply due to emboli, thrombi, or pressure that produces a macroscopic area of necrosis; the heart, brain, spleen, kidney, intestine, lung and testes are likely to be affected.
- the present invention includes methods of treating reperfusion damage by administering a therapeutically effective amount ofthe compounds having agonist activity on an LPA receptor to a patient in need of such therapy.
- the invention further encompasses a method of reducing the damage associated with myocardial and cerebral infarctions for patients with a high risk of heart attack and stroke by administering a therapeutically effective amount ofthe compounds having agonist activity on an LPA receptor to a patient in need of such therapy.
- treatment of such damage is by parenteral administration of such compounds.
- any other suitable method can be used, however, for instance, direct cardiac injection in the case of myocardial infarct.
- Devices for such injection are known in the art, for instance the Aboject cardiac syringe.
- the invention further provides methods of limiting and preventing apoptosis in cells, or otherwise preserving cells, during the culture or maintenance of mammalian organs, tissues, and cells, by the addition of an effective amount ofthe compounds having agonist activity on an LPA receptor to any media or solutions used in the art of culturing or maintaining mammalian organs, tissues, and cells.
- the invention further encompasses media and solutions known in the art of culturing and maintaining mammalian organs, tissues and cells, which include an amount ofthe compounds having agonist activity on an LPA receptor which is effective to preserve or restore cell, tissue or organ function, or limit or prevent apoptosis ofthe cells in culture.
- These aspects ofthe invention encompass mammalian cell culture media including an effective amount of at least one compounds having agonist activity on an LPA receptor and the use of such media to preserve or restore cell, tissue or organ function, or to limit or prevent apoptosis in mammalian cell culture.
- An effective amount is one which decreases the rate of apoptosis and/or preserves the cells, tissue or organ.
- Such compounds can limit or prevent apoptosis under circumstances in which cells are subjected to mild traumas which would normally stimulate apoptosis.
- exemplary traumas can include, but are not limited to, low level inadiation, thawing of frozen cell stocks, rapid changes in the temperature, pH, osmolarity, or ion concentration of culture media, prolonged exposure to non-optimal temperature, pH, osmolarity, or ion concentration ofthe culture media, exposure to cytotoxins, disassociation of cells from an intact tissue in the preparation of primary cell cultures, and serum deprivation (or growth in serum- free media).
- the invention encompasses compositions comprising tissue culture medium and an effective amount ofthe compounds having agonist activity on an LPA receptor.
- Serum-free media to which the compositions can be added as anti- apoptotic media supplements include, but are not limited to, AIM V(P Media, Neuman and Tytell's Serumless Media, Trowell's T8 Media, Waymouth's MB 752/1 and 705/1 Media, and Williams' Media E.
- suitable mammalian cell culture media to which the compounds having agonist activity on an LPA receptor can be added as anti-apoptotic media supplements include, but are not limited to, Basal Media Eagle's, Fischer's Media, McCoy's Media, Media 199, RPMI Media 1630 and 1640, Media based on F-10 & F-12 Nutrient Mixtures, Leibovitz's L-15 Media, Glasgow Minimum Essential Media, and Dulbecco's Modified Eagle Media. Mammalian cell culture media to which the compounds having agonist activity on an LPA receptor can be added as anti-apoptotic media supplements include, but are not limited to, Basal Media Eagle's, Fischer's Media, McCoy's Media, Media 199, RPMI Media 1630 and 1640, Media based on F-10 & F-12 Nutrient Mixtures, Leibovitz's L-15 Media, Glasgow Minimum Essential Media, and Dulbecco's Modified Eagle Media. Mammalian cell culture media to which the compounds having agonist activity
- LPA receptor can be added further include any media supplement known in the art.
- exemplary supplmenets include, but are not limited to, sugars, vitamins, hormones, metalloproteins, antibiotics, antimycotics, growth factors, lipoproteins, and sera.
- the invention further encompasses solutions for maintaining mammalian organs prior to transplantation, which solutions include an effective amount ofthe compounds having agonist activity on an LPA receptor, and the use of such solutions to preserve or restore organ function or to limit or prevent apoptosis in treated mammalian organs during their surgical removal and handling prior to transplantation.
- the solutions can be used to rush, perfuse and/or store the organs.
- concentrations ofthe compounds (having agonist activity on an LPA receptor) required to limit or prevent damage to the organs can be determined empirically by one skilled in the art by methods known in the art.
- the compounds having agonist activity on an LPA receptor can be topically applied to the skin to treat a variety of dermatologic conditions. These conditions include, but are not limited to, hair loss and wrinkling due to age and/or photo damage.
- the present invention also encompasses, therefore, methods of treating dermatological conditions.
- hair loss can be caused by apoptosis ofthe cells ofthe hair follicles (Stenn et al., 1994).
- the compounds having agonist activity on an LPA receptor are suitable for use in topical treatment ofthe skin to prevent continued hair loss.
- the various dermatologic conditions are preferably treated by topical application of an effective amount of a compound having agonist activity on an LPA receptor (or compositions which contain them).
- An effective amount of such compounds is one which ameliorates or diminishes the symptoms ofthe dermatologic conditions.
- the treatment results in resolution ofthe dermatologic condition or restoration of normal skin function; however, any amelioration or lessening of symptoms is encompassed by the invention.
- LPA 18:1, DGPP, Ser-PA, and Tyr-PA were obtained from Avanti Polar Lipids (Alabaster, AL). Melting points were determined on a Thomas-Hoover capillary melting point apparatus and are unconected.
- Example 7 Analysis of Compounds for LPA Receptor Agonist or Antagonist Activity
- Compounds were tested for their ability to induce or inhibit LPA- induced calcium transients in RH7777 rat hepatoma cells stably expressing LPAi, LPA2, and LPA3 receptors and in PC-3 that express LPA1-3 endogenously, using a FlexStation II automated fluorometer (Molecular Devices, Sunnyvale, CA) (Fischer et al, 2001; Virag et al., 2003).
- RH7777 cells stably expressing either LPAi, LPA2 or LPA3 (Fischer et 2001 ; Virag et al., 2003) or PC-3 cells were plated on poly-D lysine-coated black wall clear bottom 96-well plates (Becton Dickinson, San Jose, CA) with a density of 50000 cells/well, and cultured overnight.
- the culture medium (DMEM containing 10% FBS) was then replaced with modified Krebs solution (120 mM NaCl, 5 mM KC1, 0.62 mM
- N-acyl serine phosphoric acid and N-acyl tyrosine phosphoric acid were originally identified as inhibitors of LPA-induced platelet aggregation (Sugiura et al., 1994) and inhibitors of the LPA induced CF cunent in Xenopus oocytes (Liliom et al., 1996).
- Ser-PA was found to be an LP A-like agonist (Hooks et al., 1998). It was also shown to be an agonist at LPAi and LPA2 when these receptor subtypes were heterologously expressed in TAg-Jurkat T-cells (An et al., 1998b).
- VPC 12249 is a 2-substituted analog ofthe N-acyl ethanolamide phosphate that was identified as a subtype-selective inhibitor ofthe LPAi and LPA3 receptors, using a GTP ⁇ S-load ng assay with cell membranes isolated from HEK293T cells expressing LPAi, LPA2, or LPA3.
- LPA was shown to be an agonist ofthe nuclear transcription factor PPAR ⁇ (Mclntyre et al., 2003). Many agents have been reported to activate PPAR ⁇ , including thiazolidinedione family represented by Rosiglitazone, oxidized phospholipids, fatty acids, eicosanoids, and oxidized LDL.
- PPAR ⁇ activation is different from GPCRs.
- the present study extended the validity of our previously described two-point contact model as the minimal requirement to elicit specific interactions with LPA GPCRs, and provides further refinement ofthe minimal pharmacophore FAP by identifying modifications that allowed the synthesis of a pan-agonist and a pan- antagonist and several subtype-selective ligands.
- a systematic SAR study ofthe FAP pharmacophore with phosphonate, thiophosphate and introduction of unsaturation in the side chain outlined important principles for the design of subtype-selective LPA receptor agonists and antagonists.
- RH7777 cells expressing each LPA receptor individually were consistent with results obtained from PC-3 cells that endogenously express LPA1-3 receptors.
- FAPs also activate nuclear transcription factor PPAR ⁇ with an SAR different from LPA GPCR.
- oleoyl-thiophosphate (8g) was synthesized and identified as a novel pan-agonist at all three LPA receptors confirming the previously predicted necessity for an LPA1-3 agonist to possess both appropriate charge and side chain (length and unsaturation).
- E max maximal efficacy ofthe drug / maximal efficacy of LPA 18:1, expressed as the percentage.
- s Reported Ki values of DGPP are 106 nM and 6.6 ⁇ M at LPA3 and LPAI, respectively (Hasegawa et al., 2003).
- h Reported Ki values of Kil6425 are 250 nM, 360 nM and 5.6 ⁇ M at LPAI, LPA3 and LPA2, respectively (Virag et al., 2003).
- Reported Ki values of VPC12249 are 137 nM and 428 nM at LPAI and LPA3, respectively (Ohta et al., 2003).
- Example 8 In vitro Evaluation of Compound 8g For Protection of Intestinal Epithelial Cells Against Radiation or Chemotherapy Induced Apoptosis
- the experimental procedure utilized was substantially the same as that reported in Deng et al. (2002) and Deng et al., (2003). Basically, IEC-6 cells were grown in DMEM medium supplemented with 5% fetal bovine serum, insulin (10 ⁇ g/ml), gentamycin sulfate (50 ⁇ g/ml), and incubated at 37 °C in a humidified 90% air- 10% CO 2 atmosphere. Medium was changed every other day. Sub-confluent cells were washed twice and replaced by
- IEC-6 cell apoptosis was induced via either ⁇ -irradiation or chemotherapy. 20 Gy single dose of [ 137 Cs] source ⁇ -irradiation was used in all experiments. Serum starved IEC-6 cells were pretreated with LPA, FAP 12, or compound 8g (FAP 18:1 d9) for 15 minutes and then irradiated with a Mark I Model
- mice received either 250 ⁇ l of 1 mM LPA complexed with 100 ⁇ M BSA dissolved in Hanks basal salt solution or the BSA vehicle alone 2 h prior to irradiation.
- mice were euthanized with carbon dioxide inhalation 4 h after irradiation and the small intestine was dissected and fixed in neutral phosphate buffered isotonic 10% formalin.
- Four ⁇ 3- to 4-mm long segments from the small intestine were embedded in paraffin, 5 ⁇ m thick sections were cut and stained with hematoxilin and eosin. The number of surviving crypts was counted 3.5 days after irradiation.
- FAP 18:ld9 (200 ⁇ M into the stomach 2h prior irradiation) significantly (P >0.01) enhanced crypt survival in the irradiated animals (Figure 6).
- the effect of FAP was dose-dependent ( Figure 7).
- the effect of FAP 18:1 d9 was present in the jejunum and ileum and exceeded that of LPA ( Figure 8).
- Jalink et al. "Inhibition of lysophosphatidate- and thrombin-induced neurite retraction and neuronal cell rounding by ADP ribosylation ofthe small GTP-binding protein Rho," J Cell Biol. 126:801-810 (1994b). Jalink et al., “Lysophosphatidic acid-induced Ca + mobilization in human A431 cells: structure-activity analysis,” Biochem. J. 307:609-616 (1995).
- Kimura et al. "Effect of sphingosine and its N-methyl derivatives on oxidative burst, phagokinetic activity, and trans-endothelial migration of human monurophils,"5z “ 0c/zem. Pharmacol. 44:1585-1595 (1992). Kimura et al., "Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho- kinase),” Science 273:245-248 (1996).
- LPA Lysophosphatidic Acid
- Mills et al. "A putative new growth factor in ascitic fluid from ovarian cancer patients: identification, characterization, and mechanism of action," Cancer Res. 48:1066-1071 (1988). Mills et al., "Ascitic fluid from human ovarian cancer patients contains growth factors necessary for intraperitoneal growth of human ovarian adenocarcinoma cells," J. Clin. Invest. 86:851-855 (1990).
- Miyata et al. "New wound-healing model using cultured corneal endothelial cells: Quantitative study of healing process," Jpn. J. Opthalmol, 34:257-266 (1990). Moolenaar, "G-protein-coupled receptors, phosphoinositide hydrolysis, and cell proliferation," Cell Growth Differ. 2:359-364 (1991).
- Ohkawara et al. In: Biochemistiy of Cutaneous Epithelial Differentiation, Seiji et al, eds., University Park Press, Baltimore, 1977, pp. 274-278.
- Ohta et al. "Kil6425, a Subtype-Selective Antagonist for Edg-Family Lysophosphatidic Acid Receptors. Mol. Pharmacol. 64:994- 1005 (2003).
- van Corven et al. "Lysophosphatidic-induced cell proliferation: identification and dissection of signaling pathways mediated by G proteins,” Cell 59:45-54 (1989).
- van Corven et al. "Mitogenic action of lysophosphatidic acid and phosphatidic acid on fibroblasts: Dependence on acyl-chain length and inhibition by suramin,” Biochem. J. 281:163-169 (1992).
- van der Bend et al. "The biologically active phospholipid, lysophosphatidic acid, induces phosphatidylcholine breakdown in fibroblasts via activation of phospholipase D: Comparison with the response to endothelin,” Biochem. J. 285:235-240 (1992a).
- van der Bend et al. "Identification of a putative membrane receptor for the bioactive phospholipid, lysophosphatidic acid,” EMBO. 11:2495-2501 (1992b).
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US2735832A (en) * | 1956-02-21 | Bx s sx p px s sx e e | ||
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US20030130237A1 (en) * | 2000-03-17 | 2003-07-10 | Miller Duane D. | LPA receptor agonists and antagonists and methods of use |
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US20060009507A1 (en) | 2006-01-12 |
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US20080090783A1 (en) | 2008-04-17 |
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KR101390040B1 (en) | 2014-04-29 |
JP2007508324A (en) | 2007-04-05 |
EP1678096B1 (en) | 2012-01-04 |
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US7217704B2 (en) | 2007-05-15 |
KR20060118469A (en) | 2006-11-23 |
US20120135967A1 (en) | 2012-05-31 |
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AU2004278042A1 (en) | 2005-04-14 |
CA2540809C (en) | 2013-09-24 |
EP2433946A1 (en) | 2012-03-28 |
US7947665B2 (en) | 2011-05-24 |
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