CN101143868A - Aldose reductase inhibitor structure and use - Google Patents
Aldose reductase inhibitor structure and use Download PDFInfo
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- CN101143868A CN101143868A CNA2007101213255A CN200710121325A CN101143868A CN 101143868 A CN101143868 A CN 101143868A CN A2007101213255 A CNA2007101213255 A CN A2007101213255A CN 200710121325 A CN200710121325 A CN 200710121325A CN 101143868 A CN101143868 A CN 101143868A
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- aldose reductase
- compound
- reductase inhibitor
- present
- inhibition
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Abstract
The present invention discloses the structure of a class of hydantoin type aldose reductase inhibitor and applications. The compound structure provided by the present invention is shown as the formula on the right, the inhibitory activity can be applied to the synthesis of aldose reductase inhibitors (ARIs) and the research on the inhibitory function of aldose reductase, the compound provided by the present invention can be used as an aldose reductase inhibitor to be applied to the treatment of diabetes complications, and can be widely applied in the fields of chemical biology, biomedicine and biological engineering.
Description
Technical field
The present invention relates to novel aldose reductase inhibitor, its preparation method and to the restraining effect of aldose reductase (AR) is applied to chemicobiology, biomedicine and bioengineering field.
Background technology
A large amount of animals and clinical experiment have proved that aldose reductase inhibitor (ARIs) is very effective to the treatment diabetic complication.In past 30 years, have at least 14 kinds of ARIs to be proved to be very effectively and by the II phase clinical.The Epalrestat that has the most effectively gone on the market in Japan and entered clinical Fidarestat and AS-3201 of III phase wherein.And wherein Fidarestat is proved to be more effective than the Epalrestat that has gone on the market, and its inhibition effect in vivo will be higher than Epalrestat far away.The ARIs of all discoveries at present mainly is combined in the known catalytic activity position of AR.It is reported
[1], may have the active combining site of on-catalytic near the catalytic activity position of enzyme, not only can strengthen inhibition to the combination at these nonactive positions, and selection of inhibitors can strengthen greatly also.Based on above-mentioned background, the present invention as precursor structure, has designed and synthesized a class novel cpd with Fidarestat, and estimates, determined the restraining effect of compound to AR.
Summary of the invention
The object of the present invention is to provide a class new AR is had compound that suppresses ability more by force and uses thereof.
Compound provided by the present invention is a compound 2, and its structural formula is:
The synthetic method of compound 2 is with compound 1
[2](for prior art) makes than linked reaction takes place under DCC catalysis with 1: 1.2 molar equivalent with Ursol D.This preparation process can be expressed as follows with the molecular structure reaction formula:
In the reaction formula compound 1 be (2S, 4S)-6-fluoro-2 ', 5 '-dioxy spiral shell [chroman-4,4 '-imidazolidine]-2-carboxylic acid.
The title of compound 2a of the present invention, structure and molecular weight are as shown in table 1.
Title, structure and the molecular weight of table 1 compound 2a
To the aldose reductase inhibition activity measuring method: the AR that proposes from the mouse eyes is partly purified, tested new synthetic compound 2a then,, use fidarestat compound in contrast in the active ability of vitro inhibition AR (as shown in table 2).Test in the variation that 340nm (for the absorption of AR coenzyme NADP 11) locates absorbancy with ultraviolet spectrophotometer monitoring reaction liquid.
Table 2 compound 2a and fidarestat are in external inhibition ability to mouse lens AR
| Compound | Suppress percentage ratio (%) | IC 50 a (μM) | |||||
| 10 -8M | 3.3× 10 -8 M | 5×10 -8 M | 10 -7M | 10 -6 M | 10 -5M | ||
| 2a | 13 | --- b | --- b | 36 | 40 | 81 | 0.42 |
| fidarestat | 26 | --- b | 42 | 88 | --- b | --- b | 0.034 |
aIC
50(μ M) is value measured in the experimental system of implementing in the present invention (95%C.L.)
bUnder this concentration, do not measure
Compound provided by the present invention and inhibition activity can be used for the synthetic of aldose reductase inhibitor and reach the inhibiting research of aldose reductase, can be used as aldose reductase inhibitor uses in the treatment diabetic complication, and in chemicobiology, biomedicine and bioengineering field are with a wide range of applications.
Embodiment
Embodiment 1
The preparation of compound 2:
Can get raw material 1 according to the method in the former document [2], make compound 2 with raw material 1 again
The preparation method of compound 2 is approximate, with compound (2S, 4S)-6-fluoro-2 ', 5 '-dioxy spiral shell [chroman-4,4 '-imidazolidine]-2-amide group-to the example that is prepared as of aniline 2a.
1, (100mg 0.36mmol), dissolves in THF, adds HOBt (59mg, 0.50mmol), adds DCC (152mg 0.72mmol) then with raw material 1.
2, the reaction stirring at room is 20 minutes, and (46.7mg 0.43mmol), stirs after 5 hours, and TLC checks (chloroform/methanol=10/1), finds Rf=0.60 (corresponding product 2a) under the ultraviolet, and reaction mixture is filtered, and filters white precipitate DCU to add Ursol D.
3, column chromatography (methylene chloride=25/1) carries out purifying to thick product and obtains product 2a (64mg, 46/%), pale yellow powder.
Institute's synthetic compound all passes through ESI mass spectrum (MS) in the enforcement, and nuclear magnetic resonance spectrum (1HNMR) is analyzed and ultimate analysis is identified.
Implement the step of The compounds of this invention to aldose reductase inhibition activity:
1, preparation buffered soln: compound concentration is NaH2P04 and the Na2HP04 solution of 0.2mol/L respectively earlier, gets the two 81.5ml then respectively, and it is 200ml that 18.5ml is diluted with water to final volume, promptly obtains the phosphate buffer soln of 0.1mol/L pH=6.2.
2, compound concentration is 0.104 mM NADPH solution (with a buffered soln as solvent).
3, compound concentration is 10mM D, L-Glycerose solution (with buffered soln as solvent).
4, from the mouse eyeball that normally kills, take out lens rapidly, in the Glas-Potter homogenizer, add 3 times (0.4ml/lens) then in cold deionized water (0-4 ℃) homogenate of its volume.Homogenate in refrigerated centrifuge with 12000 * g rotating speed, 0-4 ℃ temperature, centrifugal 30min. gets supernatant liquor at last, is the aqueous solution of AR, is used for the enzyme test of living.
5, under 30 ℃ temperature, in 1ml test cuvette, add 0.25mL 0.104mM NADPH respectively, 0.25mL0.1M phosphate buffer soln (pH=6.2), the enzyme liquid that 0.1mL extracted, 0.15mL deionized water.With reference to adding 0.25mL 0.104mM NADPH, 0.50mL 0.1M phosphate buffer soln (pH=6.2), the enzyme liquid that 0.1mL extracted, 0.15mL deionized water in the cuvette.Then two cuvettes that contain above-mentioned mixed solution are placed under 30 ℃ of conditions insulation 10min.Adding the 0.25mL10mM substrate at last in the test cuvette is D, and L-Glycerose begins reaction, monitors 5min with ultraviolet spectrophotometer at 340nm.From the gained data, be the longitudinal axis with the absorbancy, the time is horizontal state, can get a straight line, tries to achieve this collinear slope, is designated as I
0, represent enzyme to live.The active optimum value of enzyme is to be in the NADPH absorbancy to change in the scope of 0.011 ± 0.0010 absorbance unit/min, if not in this scope, makes it reach this scope by dilution enzyme liquid.Will add the contrast cuvette to the test cuvette is in order to proofread and correct because non-enzyme factor the oxidation of the NADPH that (also can oxidation NADPH such as oxygen in the air) be caused.
6, the compound test that suppresses percentage ratio is similar with surveying the method that enzyme lives, just when not adding substrate, and be at the test cuvette and respectively add the test compound solution of 5 μ L in reference to cuvette.Gained collinear slope is designated as Ix.Calculate inhibition percentage ratio under can this concentration according to following formula then.
I％＝(|I
0-I
x|/|I
0|)×100％
The compound solution of replicate measurement different concns, calculate the inhibition percentage ratio of respective concentration respectively, can obtain " inhibition percentage ratio " straight line, read from figure then that to suppress percentage ratio be the concentration logarithm of 50% correspondence " concentration logarithm ", antilogarithm get final product IC50.
Claims (2)
1. aldose reductase inhibitor structure and purposes is characterized in that:
The structure of compound 2 is:
2. aldose reductase inhibitor structure as claimed in claim 1 and purposes is characterized in that: compound 2 is as the application of aldose reductase inhibitor at the treatment diabetic complication.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007101213255A CN101143868A (en) | 2007-09-04 | 2007-09-04 | Aldose reductase inhibitor structure and use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CNA2007101213255A CN101143868A (en) | 2007-09-04 | 2007-09-04 | Aldose reductase inhibitor structure and use |
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| CN101143868A true CN101143868A (en) | 2008-03-19 |
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| CNA2007101213255A Pending CN101143868A (en) | 2007-09-04 | 2007-09-04 | Aldose reductase inhibitor structure and use |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017223179A1 (en) | 2016-06-21 | 2017-12-28 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and methods of use thereof |
| US10639306B2 (en) | 2010-07-16 | 2020-05-05 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and uses thereof |
| WO2020205846A1 (en) | 2019-04-01 | 2020-10-08 | Applied Therapeutics Inc. | Inhibitors of aldose reductase |
| US11590131B2 (en) | 2017-07-28 | 2023-02-28 | Applied Therapeutics, Inc. | Compositions and methods for treating galactosemia |
-
2007
- 2007-09-04 CN CNA2007101213255A patent/CN101143868A/en active Pending
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US10639306B2 (en) | 2010-07-16 | 2020-05-05 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and uses thereof |
| US11529349B2 (en) | 2010-07-16 | 2022-12-20 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and uses thereof |
| US11730737B2 (en) | 2010-07-16 | 2023-08-22 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and uses thereof |
| WO2017223179A1 (en) | 2016-06-21 | 2017-12-28 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and methods of use thereof |
| US10150779B2 (en) | 2016-06-21 | 2018-12-11 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and methods of use thereof |
| US10647726B2 (en) | 2016-06-21 | 2020-05-12 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and methods of use thereof |
| US10870658B2 (en) | 2016-06-21 | 2020-12-22 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and methods of use thereof |
| EP3757107A1 (en) | 2016-06-21 | 2020-12-30 | The Trustees of Columbia University in the City of New York | 4-oxo-3,4-dihydrothieno[3,4-d]pyridazine compounds as aldose reductase inhibitors and methods of use thereof |
| US11498925B2 (en) | 2016-06-21 | 2022-11-15 | The Trustees Of Columbia University In The City Of New York | Aldose reductase inhibitors and methods of use thereof |
| EP4316603A2 (en) | 2016-06-21 | 2024-02-07 | The Trustees of Columbia University in the City of New York | 4-oxo-3,4-dihydrothieno[3,4-d]pyridazine compounds as aldose reductase inhibitors and methods of use thereof |
| US11590131B2 (en) | 2017-07-28 | 2023-02-28 | Applied Therapeutics, Inc. | Compositions and methods for treating galactosemia |
| WO2020205846A1 (en) | 2019-04-01 | 2020-10-08 | Applied Therapeutics Inc. | Inhibitors of aldose reductase |
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Open date: 20080319 |