Discovery of 2-[4-{{2-(2 S, 5 R)-2-Cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl] amino]-4-methyl-1-piperidinyl]-4-pyridinecarboxylic Acid (ABT-279): A Very Potent, …

…, MG Fickes, L Bhagavatula, T McDermott…

Index: Madar, David J.; Kopecka, Hana; Pireh, Daisy; Yong, Hong; Pei, Zhonghua; Li, Xiaofeng; Wiedeman, Paul E.; Djuric, Stevan W.; Von Geldern, Thomas W.; Fickes, Michael G.; Bhagavatula, Lakshmi; McDermott, Todd; Wittenberger, Steven; Richards, Steven J.; Longenecker, Kenton L.; Stewart, Kent D.; Lubben, Thomas H.; Ballaron, Stephen J.; Stashko, Michael A.; Long, Michelle A.; Wells, Heidi; Zinker, Bradley A.; Mika, Amanda K.; Beno, David W. A.; Kempf-Grote, Anita J.; Polakowski, James; Segreti, Jason; Reinhart, Glenn A.; Fryer, Ryan M.; Sham, Hing L.; Trevillyan, James M. Journal of Medicinal Chemistry, 2006 , vol. 49, # 21 p. 6416 - 6420

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Citation Number: 44

Abstract

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (K iDPP-IV= 1.0 nM) and selective (K iDPP8> 30 μM; K iDPP9> 30 μM) clinical candidate, ABT-279, ...