title: Identification of 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones: a new class of potent, selective, and orally active non-peptide dipeptidyl peptidase IV inhibitors that form a unique interaction with Lys554.
abstract: The design, synthesis, and structure-activity relationships of a new class of potent and orally active non-peptide dipeptidyl peptidase IV (DPP-4) inhibitors, 3-aminomethyl-1,2-dihydro-4-phenyl-1-isoquinolones, are described. We hypothesized that the 4-phenyl group of the isoquinolone occupies the S1 pocket of the enzyme, the 3-aminomethyl group forms an electrostatic interaction with the S2 pocket, and the introduction of a hydrogen bond donor onto the 6- or 7-substituent provides interaction with the hydrophilic region of the enzyme. Based on this hypothesis, intensive research focused on developing new non-peptide DPP-4 inhibitors has been carried out. Among the compounds designed in this study, we identified 2-[(3-aminomethyl-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydro-6-isoquinolinyl)oxy]acetamide (35a) as a potent, selective, and orally bioavailable DPP-4 inhibitor, which exhibited in vivo efficacy in diabetic model rats. Finally, X-ray crystallography of 35a in a complex with the enzyme validated our hypothesized binding mode and identified Lys554 as a new target-binding site available for DPP-4 inhibitors.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi 2-Chome Yodogawa-ku, Yodogawa-ku, Osaka 532-8686, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Banno
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Miyamoto
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Sasaki
authors.forename: Satoru
authors.initials: S
authors.lastname: Oi
authors.forename: Tomoko
authors.initials: T
authors.lastname: Asakawa
authors.forename: Osamu
authors.initials: O
authors.lastname: Kataoka
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: Miyuki
authors.initials: M
authors.lastname: Funami
authors.forename: Michiko
authors.initials: M
authors.lastname: Tawada
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: D000284:Administration, Oral; D000818:Animals; D001786:Blood Glucose; D018938:Caco-2 Cells; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D018819:Dipeptidyl Peptidase 4 / Q000032:analysis / Q000187:drug effects*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000032:analysis / Q000037:antagonists & inhibitors / Q000187:drug effects; D015195:Drug Design; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D007546:Isoquinolines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D058990:Molecular Targeted Therapy; D010455:Peptides / Q000378:metabolism; D015363:Quinolones / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: C569807:2-((3-(aminomethyl)-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)oxy)acetamide; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007546:Isoquinolines; D010455:Peptides; D015363:Quinolones; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases; C100151:dipeptidyl peptidase II; D018819:Dipeptidyl Peptidase 4