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.

Article Details

Citation

Copy to clipboard

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

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.

J Med Chem. 2006 Oct 19;49(21):6416-20.

PubMed ID

17034148 [ View in PubMed

]

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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Vildagliptin	Dipeptidyl peptidase 4	Ki (nM)	4	7.5	22	Details