title: (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.
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.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., Rahway, New Jersey 07065, USA. dooseop_kim@merck.com
authors.forename: Dooseop
authors.initials: D
authors.lastname: Kim
authors.forename: Liping
authors.initials: L
authors.lastname: Wang
authors.forename: Maria
authors.initials: M
authors.lastname: Beconi
authors.forename: George J
authors.initials: GJ
authors.lastname: Eiermann
authors.forename: Michael H
authors.initials: MH
authors.lastname: Fisher
authors.forename: Huaibing
authors.initials: H
authors.lastname: He
authors.forename: Gerard J
authors.initials: GJ
authors.lastname: Hickey
authors.forename: Jennifer E
authors.initials: JE
authors.lastname: Kowalchick
authors.forename: Barbara
authors.initials: B
authors.lastname: Leiting
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lyons
authors.forename: Frank
authors.initials: F
authors.lastname: Marsilio
authors.forename: Margaret E
authors.initials: ME
authors.lastname: McCann
authors.forename: Reshma A
authors.initials: RA
authors.lastname: Patel
authors.forename: Aleksandr
authors.initials: A
authors.lastname: Petrov
authors.forename: Giovanna
authors.initials: G
authors.lastname: Scapin
authors.forename: Sangita B
authors.initials: SB
authors.lastname: Patel
authors.forename: Ranabir Sinha
authors.initials: RS
authors.lastname: Roy
authors.forename: Joseph K
authors.initials: JK
authors.lastname: Wu
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Wyvratt
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
authors.forename: Lan
authors.initials: L
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; D001665:Binding Sites; D001671:Biochemistry / Q000379:methods; D001786:Blood Glucose / Q000032:analysis; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D005934:Glucagon / Q000097:blood / Q000187:drug effects; D052216:Glucagon-Like Peptide 1; D005951:Glucose Tolerance Test; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008958:Models, Molecular; D010446:Peptide Fragments / Q000097:blood / Q000187:drug effects; D011487:Protein Conformation; D011498:Protein Precursors / Q000097:blood / Q000187:drug effects; D011719:Pyrazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D000068900:Sitagliptin Phosphate; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D010446:Peptide Fragments; D011498:Protein Precursors; D011719:Pyrazines; D014230:Triazoles; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D018819:Dipeptidyl Peptidase 4; D000068900:Sitagliptin Phosphate