title: Discovery of potent, selective, and orally bioavailable quinoline-based dipeptidyl peptidase IV inhibitors targeting Lys554.
abstract: Dipeptidyl peptidase IV (DPP-4) inhibition is a validated therapeutic option for type 2 diabetes, exhibiting multiple antidiabetic effects with little or no risk of hypoglycemia. In our studies involving non-covalent DPP-4 inhibitors, a novel series of quinoline-based inhibitors were designed based on the co-crystal structure of isoquinolone 2 in complex with DPP-4 to target the side chain of Lys554. Synthesis and evaluation of designed compounds revealed 1-[3-(aminomethyl)-4-(4-methylphenyl)-2-(2-methylpropyl)quinolin-6-yl]piperazine-2,5-dione (1) as a potent, selective, and orally active DPP-4 inhibitor (IC₅₀=1.3 nM) with long-lasting ex vivo activity in dogs and excellent antihyperglycemic effects in rats. A docking study of compound 1 revealed a hydrogen-bonding interaction with the side chain of Lys554, suggesting this residue as a potential target site useful for enhancing DPP-4 inhibition.
authors: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohomachi 2-chome, Yodogawa-ku, Osaka 532-8686, Japan.
authors: Hironobu
authors: H
authors: Maezaki
authors: Yoshihiro
authors: Y
authors: Banno
authors: Yasufumi
authors: Y
authors: Miyamoto
authors: Yusuke
authors: Y
authors: Moritoh
authors: Yuusuke
authors: Y
authors: Moritou
authors: Tomoko
authors: T
authors: Asakawa
authors: Osamu
authors: O
authors: Kataoka
authors: Koji
authors: K
authors: Takeuchi
authors: Nobuhiro
authors: N
authors: Suzuki
authors: Koji
authors: K
authors: Ikedo
authors: Takuo
authors: T
authors: Kosaka
authors: Masako
authors: M
authors: Sasaki
authors: Shigetoshi
authors: S
authors: Tsubotani
authors: Akiyoshi
authors: A
authors: Tani
authors: Miyuki
authors: M
authors: Funami
authors: Yoshio
authors: Y
authors: Yamamoto
authors: Michiko
authors: M
authors: Tawada
authors: Kathleen
authors: K
authors: Aertgeerts
authors: Jason
authors: J
authors: Yano
authors: Satoru
authors: S
authors: Oi
mesh_terms: D000818:Animals; D018938:Caco-2 Cells; D002460:Cell Line; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy*; D018819:Dipeptidyl Peptidase 4 / Q000737:chemistry / Q000378:metabolism*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004285:Dogs; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D008239:Lysine / Q000378:metabolism; D011804:Quinolines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011804:Quinolines; D018819:Dipeptidyl Peptidase 4; D008239:Lysine