title: Discovery of a 3-pyridylacetic acid derivative (TAK-100) as a potent, selective and orally active dipeptidyl peptidase IV (DPP-4) inhibitor.
abstract: Inhibition of dipeptidyl peptidase IV (DPP-4) is an exciting new approach for the treatment of diabetes. To date there has been no DPP-4 chemotype possessing a carboxy group that has progressed into clinical trials. Originating from the discovery of the structurally novel quinoline derivative 1, we designed novel pyridine derivatives containing a carboxy group. In our design, the carboxy group interacted with the targeted amino acid residues around the catalytic region and thereby increased the inhibitory activity. After further optimization, we identified a hydrate of [5-(aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-methylphenyl)pyridin-3-yl]acetic acid (30c) as a potent and selective DPP-4 inhibitor. The desired interactions with the critical active-site residues, such as a salt-bridge interaction with Arg125, were confirmed by X-ray cocrystal structure analysis. In addition, compound 30c showed a desired preclinical safety profile, and it was encoded as TAK-100.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-Chome, Osaka 532-8686, Japan.
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Banno
authors.forename: Tohru
authors.initials: T
authors.lastname: Yamashita
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Satoru
authors.initials: S
authors.lastname: Oi
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Moritoh
authors.forename: Tomoko
authors.initials: T
authors.lastname: Asakawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Kataoka
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Yashiro
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Suzuki
authors.forename: Koji
authors.initials: K
authors.lastname: Ikedo
authors.forename: Takuo
authors.initials: T
authors.lastname: Kosaka
authors.forename: Shigetoshi
authors.initials: S
authors.lastname: Tsubotani
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Tani
authors.forename: Masako
authors.initials: M
authors.lastname: Sasaki
authors.forename: Miyuki
authors.initials: M
authors.lastname: Funami
authors.forename: Michiko
authors.initials: M
authors.lastname: Amano
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Kathleen
authors.initials: K
authors.lastname: Aertgeerts
authors.forename: Jason
authors.initials: J
authors.lastname: Yano
authors.forename: Hironobu
authors.initials: H
authors.lastname: Maezaki
mesh_terms: D000085:Acetates / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D004285:Dogs; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007004:Hypoglycemic Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008958:Models, Molecular; D011487:Protein Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: C575633:5-(aminomethyl)-6-(2,2-dimethylpropyl)-2-ethyl-4-(4-methylphenyl)pyridin-3-ylacetic acid; D000085:Acetates; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D011725:Pyridines; D011804:Quinolines