title: Novel tetrahydropyran analogs as dipeptidyl peptidase IV inhibitors: Profile of clinical candidate (2R,3S,5R)-2- (2,5-difluorophenyl)-5-(4,6-dihydropyrrolo [3,4-c]pyrazol-5-(1H)-yl)tetrahydro-2H-pyran-3-amine (23) [corrected].
abstract: A series of novel tri-2,3,5-substituted tetrahydropyran analogs were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes. Optimization of the series provided inhibitors with good DPP-4 potency and selectivity over other peptidases (QPP, DPP8, and FAP). Compound 23, which is very potent, selective, efficacious in the diabetes PD model, and has an excellent pharmacokinetic profile, is selected as a clinical candidate.
authors: Discovery Chemistry, Merck Research Laboratories, Rahway, NJ 07065, USA. Tesfaye_Biftu@merck.com
authors: Tesfaye
authors: T
authors: Biftu
authors: Xiaoxia
authors: X
authors: Qian
authors: Ping
authors: P
authors: Chen
authors: Dennis
authors: D
authors: Feng
authors: Giovanna
authors: G
authors: Scapin
authors: Ying-Duo
authors: YD
authors: Gao
authors: Jason
authors: J
authors: Cox
authors: Ranabir Sinha
authors: RS
authors: Roy
authors: George
authors: G
authors: Eiermann
authors: Huabing
authors: H
authors: He
authors: Kathy
authors: K
authors: Lyons
authors: Gino
authors: G
authors: Salituro
authors: Sangita
authors: S
authors: Patel
authors: Alexander
authors: A
authors: Petrov
authors: Feng
authors: F
authors: Xu
authors: Shiyao Sherrie
authors: SS
authors: Xu
authors: Bei
authors: B
authors: Zhang
authors: Charles
authors: C
authors: Caldwell
authors: Joseph K
authors: JK
authors: Wu
authors: Kathy
authors: K
authors: Lyons
authors: Ann E
authors: AE
authors: Weber
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D005951:Glucose Tolerance Test; D000882:Haplorhini; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis*; D006801:Humans; D020128:Inhibitory Concentration 50; D011714:Pyrans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism
chemical_list: C587539:2-(2,5-difluorophenyl)-5-(2-(methylsulfonyl)-2,6-dihydropyrrolo(3,4-c)pyrazol-5(4H)-yl)tetrahydro-2H-pyran-3-amine; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D011714:Pyrans
keywords: DPP-4 inhibitors; DPP-IV; Diabetes; Tetrahydropyran