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

Yoshihiro Banno; Yasufumi Miyamoto; Mitsuru Sasaki; Satoru Oi; Tomoko Asakawa; Osamu Kataoka; Koji Takeuchi; Nobuhiro Suzuki; Koji Ikedo; Takuo Kosaka; Shigetoshi Tsubotani; Akiyoshi Tani; Miyuki Funami; Michiko Tawada; Yoshio Yamamoto; Kathleen Aertgeerts; Jason Yano; Hironobu Maezaki

doi:10.1016/j.bmc.2011.06.059

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

Bioorg Med Chem. 2011 Aug 15;19(16):4953-70. doi: 10.1016/j.bmc.2011.06.059. Epub 2011 Jun 28.

Authors

Yoshihiro Banno¹, Yasufumi Miyamoto, Mitsuru Sasaki, Satoru Oi, Tomoko Asakawa, Osamu Kataoka, Koji Takeuchi, Nobuhiro Suzuki, Koji Ikedo, Takuo Kosaka, Shigetoshi Tsubotani, Akiyoshi Tani, Miyuki Funami, Michiko Tawada, Yoshio Yamamoto, Kathleen Aertgeerts, Jason Yano, Hironobu Maezaki

Affiliation

¹ Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85 Jusohonmachi 2-Chome Yodogawa-ku, Yodogawa-ku, Osaka 532-8686, Japan.

PMID: 21764322
DOI: 10.1016/j.bmc.2011.06.059

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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Administration, Oral
Animals
Blood Glucose
Caco-2 Cells
Diabetes Mellitus, Type 2 / drug therapy
Dipeptidyl Peptidase 4 / analysis
Dipeptidyl Peptidase 4 / drug effects*
Dipeptidyl-Peptidase IV Inhibitors / administration & dosage
Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis*
Dipeptidyl-Peptidase IV Inhibitors / chemistry
Dipeptidyl-Peptidase IV Inhibitors / pharmacology
Dipeptidyl-Peptidase IV Inhibitors / therapeutic use
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / analysis
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / drug effects
Drug Design
Female
Glucose Tolerance Test
Humans
Hypoglycemic Agents / administration & dosage
Hypoglycemic Agents / chemical synthesis*
Hypoglycemic Agents / chemistry
Hypoglycemic Agents / pharmacology
Hypoglycemic Agents / therapeutic use
Isoquinolines / administration & dosage
Isoquinolines / chemical synthesis*
Isoquinolines / pharmacology
Isoquinolines / therapeutic use
Molecular Targeted Therapy
Peptides / metabolism
Quinolones / administration & dosage
Quinolones / chemical synthesis
Quinolones / chemistry
Quinolones / pharmacology
Quinolones / therapeutic use
Rats
Rats, Wistar
Structure-Activity Relationship

Substances

2-((3-(aminomethyl)-2-(2-methylpropyl)-1-oxo-4-phenyl-1,2-dihydroisoquinolin-6-yl)oxy)acetamide
Blood Glucose
Dipeptidyl-Peptidase IV Inhibitors
Hypoglycemic Agents
Isoquinolines
Peptides
Quinolones
Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
dipeptidyl peptidase II
Dipeptidyl Peptidase 4