Structure Report for: 2I03

Longenecker, K.L., Madar, D.J

Title: 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
Madar DJ, Kopecka H, Pireh D, Yong H, Pei Z, Li X, Wiedeman PE, Djuric SW, von Geldern TW and Trevillyan JM <21 more author(s)> Madar DJ, Kopecka H, Pireh D, Yong H, Pei Z, Li X, Wiedeman PE, Djuric SW, von Geldern TW, Fickes MG, Bhagavatula L, McDermott T, Wittenberger S, Richards SJ, Longenecker KL, Stewart KD, Lubben TH, Ballaron SJ, Stashko MA, Long MA, Wells H, Zinker BA, Mika AK, Beno DW, Kempf-Grote AJ, Polakowski J, Segreti J, Reinhart GA, Fryer RM, Sham HL, Trevillyan JM (- 21)
Ref: Journal of Medicinal Chemistry, 49:6416, 2006 : PubMed
Abstract


ESTHER: Madar_2006_J.Med.Chem_49_6416
PubMedSearch: Madar 2006 J.Med.Chem 49 6416
PubMedID: 17034148
Gene_locus related to this paper: human-DPP4
Inhibitor(s) related to this paper: ABT-279

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 (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.