title: (2S,3S)-3-Amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]-pyridin-6-ylphenyl)butanamide: a selective alpha-amino amide dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
abstract: A series of beta-substituted biarylphenylalanine amides were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the metabolic profile of early analogues led to the discovery of (2S,3S)-3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-[1,2,4]triazolo[1,5-a]pyridin-6-ylphenyl)butanamide (6), a potent, orally active DPP-4 inhibitor (IC(50) = 6.3 nM) with excellent selectivity, oral bioavailability in preclinical species, and in vivo efficacy in animal models. Compound 6 was selected for further characterization as a potential new treatment for type 2 diabetes.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065, USA. scott_edmondson@merck.com
authors.forename: Scott D
authors.initials: SD
authors.lastname: Edmondson
authors.forename: Anthony
authors.initials: A
authors.lastname: Mastracchio
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Mathvink
authors.forename: Jiafang
authors.initials: J
authors.lastname: He
authors.forename: Bart
authors.initials: B
authors.lastname: Harper
authors.forename: You-Jung
authors.initials: YJ
authors.lastname: Park
authors.forename: Maria
authors.initials: M
authors.lastname: Beconi
authors.forename: Jerry
authors.initials: J
authors.lastname: Di Salvo
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.forename: Huaibing
authors.initials: H
authors.lastname: He
authors.forename: Barbara
authors.initials: B
authors.lastname: Leiting
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Leone
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Levorse
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lyons
authors.forename: Reshma A
authors.initials: RA
authors.lastname: Patel
authors.forename: Sangita B
authors.initials: SB
authors.lastname: Patel
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Petrov
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.forename: Jackie
authors.initials: J
authors.lastname: Shang
authors.forename: Ranabir Sinha
authors.initials: RS
authors.lastname: Roy
authors.forename: Aaron
authors.initials: A
authors.lastname: Smith
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wu
authors.forename: Shiyao
authors.initials: S
authors.lastname: Xu
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Thornberry
authors.forename: Ann E
authors.initials: AE
authors.lastname: Weber
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D020746:Calcium Channels, L-Type / Q000187:drug effects; D002460:Cell Line; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D009124:Muscle Proteins / Q000037:antagonists & inhibitors; D018482:Muscle, Skeletal / Q000378:metabolism; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010649:Phenylalanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D015222:Sodium Channels; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C512076:3-amino-4-(3,3-difluoropyrrolidin-1-yl)-N,N-dimethyl-4-oxo-2-(4-(1,2,4)triazolo(1,5-a)pyridin-6-ylphenyl)butanamide; D020746:Calcium Channels, L-Type; D007004:Hypoglycemic Agents; D009124:Muscle Proteins; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011480:Protease Inhibitors; C568320:SCN5A protein, human; C568321:Scn5a protein, mouse; D015222:Sodium Channels; D014230:Triazoles; D010649:Phenylalanine; D018819:Dipeptidyl Peptidase 4