title: Fused bicyclic heteroarylpiperazine-substituted L-prolylthiazolidines as highly potent DPP-4 inhibitors lacking the electrophilic nitrile group.
abstract: Hypoglycemic agents with a mechanism of depeptidyl peptidase IV (DPP-4) inhibition are suitable for once daily oral dosing. It is difficult to strike a balance between inhibitory activity and duration of action in plasma for inhibitors bearing an electrophilic nitrile group. We explored fused bicyclic heteroarylpiperazine substituted at the γ-position of the proline structure in the investigation of L-prolylthiazolidines lacking the electrophilic nitrile. Among them, 2-trifluoroquinolyl compound 8g is the most potent, long-lasting DPP-4 inhibitor (IC(50) = 0.37 nmol/L) with high selectivity against other related peptidases. X-ray crystal structure determination of 8g indicates that CH-π interactions generated between the quinolyl ring and the guanidinyl group of Arg358 enhances the DPP-4 inhibitory activity and selectivity.
authors: Research Division, Mitsubishi Tanabe Pharma Corporation, 2-2-50, Kawagishi, Toda-shi, Saitama 335-8505, Japan.
authors: Tomohiro
authors: T
authors: Yoshida
authors: Fumihiko
authors: F
authors: Akahoshi
authors: Hiroshi
authors: H
authors: Sakashita
authors: Shuji
authors: S
authors: Sonda
authors: Masahiro
authors: M
authors: Takeuchi
authors: Yoshihito
authors: Y
authors: Tanaka
authors: Mika
authors: M
authors: Nabeno
authors: Hiroyuki
authors: H
authors: Kishida
authors: Ikuko
authors: I
authors: Miyaguchi
authors: Yoshiharu
authors: Y
authors: Hayashi
mesh_terms: D000818:Animals; D001643:Bridged Bicyclo Compounds / Q000737:chemistry*; D018360:Crystallography, X-Ray; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009570:Nitriles / Q000737:chemistry*; D010879:Piperazines / Q000737:chemistry*; D011392:Proline / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D053778:Thiazolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D001643:Bridged Bicyclo Compounds; D054873:Dipeptidyl-Peptidase IV Inhibitors; D009570:Nitriles; D010879:Piperazines; D053778:Thiazolidines; D011392:Proline; D018819:Dipeptidyl Peptidase 4