4-Cyanothiazolidides as very potent, stable inhibitors of dipeptidyl peptidase IV

Bioorganic and Medicinal Chemistry Letters

Volumn 6, Issue 22, 1996, Pages 2745-2748

  Ashworth, Doreen M ^a   Atrash, Butrus ^a   Baker, Graham R ^a   Baxter, Andrew J ^a   Jenkins, Paul D ^a   Jones, D Michael ^a   Szelke, Michael ^a  

^a Chilworth Research Centre   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

DIPEPTIDYL PEPTIDASE IV; ENZYME INHIBITOR; THIAZOLIDINE DERIVATIVE;

ARTICLE; CONTROLLED STUDY; DRUG DESIGN; DRUG STABILITY; DRUG SYNTHESIS; ENZYME INHIBITION; HIGH PERFORMANCE LIQUID CHROMATOGRAPHY; HUMAN; IN VITRO STUDY;

EID: 0030593875     PISSN: 0960894X     EISSN: None     Source Type: Journal    
DOI: 10.1016/S0960-894X(96)00491-X     Document Type: Article

References (13)

1. 1) Heins, J.; Weiker, P.; Schonlein, C.; Born, I.; Hartrodt, B.; Neubert, K.; Tsuru, D.; Barth, A. Biochim. et Biophys. Acta 1988, 954, 161.
2. 2) Hegen, M.; Niedobitek, G.; Clein, C.E.; Stein H.; Fleischer, B. J. Immunol. 1990, 144, 2908.
3. 3) Schon, E.; Born, I.; Demuth, H.-U.; Faust, J.; Neubert, K.; Steinmetzer, T.; Barth, A.; Ansorge, S. Biol. Chem. Hoppe-Seyler 1991, 372, 305.
4. 4) Flentke, G.R.; Munoz, E.; Huber, B.T.; Plaut, A.G.; Kettner, C.A.; Bachovchin, W.W. Proc. Natl. Acad. Sci. USA 1991, 88, 1556.
5. 5) A review has recently been published, discussing the evidence that CD26 has important functions in the immune system. Fleischer, B. Immunology Today 1994, 15, 180.
6. 6) Patent Cooperation Treaty (PCT) WO 95/15309 (6 Dec. 1993).
7. 7) Ashworth, D.M.; Atrash, B.; Baker, G.R.; Baxter, A.J.; Jenkins, P.D.; Jones, D.M.; Szelke, M. Bioorg. Med. Chem. Lett. 1996, 6, 1163.
8. i values were determined using Dixon plots.
9. 9) The stability of the inhibitors in buffered, aqueous solution (100 mM Tris, pH 7.4) was monitored by reverse-phase HPLC. The inhibitors with half-lives of less than 48h decompose to multiple products which have not been characterised.
10. 10) Martinez, J.; Bali, J.P.; Rodriguez, M.; Castro, B.; Laur, J.; Lignon, M.-F. J. Med. Chem. 1988, 28, 1874.
11. 13C NMR and FAB mass spectrometry.
12. 12) Compound 4 is the active diastereomer of a pair separated by preparative HPLC and was assigned the (S,S) stereochemistry. The (S,R) diastereomer was inactive versus human DP-IV.
13. 13) Compounds 7 and 9 are separated diastereomers (preparative HPLC) whose absolute stereochemistry was not determined.