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(2R)-4-Oxo-4-[3-(Trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin- 7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine: A Potent, Orally Active Dipeptidyl Peptidase IV Inhibitor for the Treatment of Type 2 Diabetes

Journal of Medicinal Chemistry · 2004 · Vol. 48(1) · pp. 141–151

Dooseop Kim✉(Merck & Co., Inc., Rahway, NJ, USA (United States))Liping Wang(Merck & Co., Inc., Rahway, NJ, USA (United States))Maria Beconi(Merck & Co., Inc., Rahway, NJ, USA (United States))George J. Eiermann(Merck & Co., Inc., Rahway, NJ, USA (United States))Michael H. Fisher(Merck & Co., Inc., Rahway, NJ, USA (United States))Huaibing He(Merck & Co., Inc., Rahway, NJ, USA (United States))Gerard J. Hickey(Merck & Co., Inc., Rahway, NJ, USA (United States))Jennifer E. Kowalchick(Merck & Co., Inc., Rahway, NJ, USA (United States))Barbara Leiting(Merck & Co., Inc., Rahway, NJ, USA (United States))Kathryn A. Lyons(Merck & Co., Inc., Rahway, NJ, USA (United States))Frank Marsilio(Merck & Co., Inc., Rahway, NJ, USA (United States))Margaret E. McCann(Merck & Co., Inc., Rahway, NJ, USA (United States))Reshma A. Patel(Merck & Co., Inc., Rahway, NJ, USA (United States))Aleksandr Petrov(Merck & Co., Inc., Rahway, NJ, USA (United States))Giovanna Scapin(Merck & Co., Inc., Rahway, NJ, USA (United States))Sangita B. Patel(Merck & Co., Inc., Rahway, NJ, USA (United States))Ranabir Sinha Roy(Merck & Co., Inc., Rahway, NJ, USA (United States))Joseph K. Wu(Merck & Co., Inc., Rahway, NJ, USA (United States))Matthew J. Wyvratt(Merck & Co., Inc., Rahway, NJ, USA (United States))Bei B. Zhang(Merck & Co., Inc., Rahway, NJ, USA (United States))Lan Zhu(Merck & Co., Inc., Rahway, NJ, USA (United States))Nancy A. Thornberry(Merck & Co., Inc., Rahway, NJ, USA (United States))Ann E. Weber(Merck & Co., Inc., Rahway, NJ, USA (United States))

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Abstract

A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.

Peptidase Inhibition and Analysis Diabetes Treatment and Management Adenosine and Purinergic SignalingChemistryTrifluoromethylBioavailabilityIn vivoStereochemistryAmine gas treatingPharmacologyDipeptidyl peptidase-4 inhibitorSelectivityDiabetes mellitus

MeSH terms

Sitagliptin PhosphateAdministration, OralAnimalsBinding SitesBiochemistryBlood GlucoseDiabetes Mellitus, Type 2DogsDose-Response Relationship, DrugDrug Evaluation, PreclinicalEnzyme InhibitorsGlucagonGlucose Tolerance TestHypoglycemic AgentsMice, Inbred C57BL

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814

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20.17

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