- Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.
Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.
Journal of medicinal chemistry (2006-10-13)
David J Madar, Hana Kopecka, Daisy Pireh, Hong Yong, Zhonghua Pei, Xiaofeng Li, Paul E Wiedeman, Stevan W Djuric, Thomas W Von Geldern, Michael G Fickes, Lakshmi Bhagavatula, Todd McDermott, Steven Wittenberger, Steven J Richards, Kenton L Longenecker, Kent D Stewart, Thomas H Lubben, Stephen J Ballaron, Michael A Stashko, Michelle A Long, Heidi Wells, Bradley A Zinker, Amanda K Mika, David W A Beno, Anita J Kempf-Grote, James Polakowski, Jason Segreti, Glenn A Reinhart, Ryan M Fryer, Hing L Sham, James M Trevillyan
PMID17034148
摘要
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 (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
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