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

• Published in: Bioorganic & medicinal chemistry 2011-08, Vol.19 (16), p.4953-4970
• Main Authors: Banno, Yoshihiro, Miyamoto, Yasufumi, Sasaki, Mitsuru, Oi, Satoru, Asakawa, Tomoko, Kataoka, Osamu, Takeuchi, Koji, Suzuki, Nobuhiro, Ikedo, Koji, Kosaka, Takuo, Tsubotani, Shigetoshi, Tani, Akiyoshi, Funami, Miyuki, Tawada, Michiko, Yamamoto, Yoshio, Aertgeerts, Kathleen, Yano, Jason, Maezaki, Hironobu
• Format: Article
• Language: English
• Subjects: Administration, Oral; Animals; Anti-diabetic effects; Biological and medical sciences; Blood Glucose; Caco-2 Cells; Diabetes Mellitus, Type 2 - drug therapy; Dipeptidyl Peptidase 4 - analysis; Dipeptidyl Peptidase 4 - drug effects; Dipeptidyl peptidase IV (DPP-4); dipeptidyl-peptidase IV; 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; electrostatic interactions; Female; General and cellular metabolism. Vitamins; Glucose Tolerance Test; Humans; hydrogen bonding; hydrophilic interactions; 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; Isoquinolone; Medical sciences; Molecular Targeted Therapy; Peptides - metabolism; Pharmacology. Drug treatments; Quinolones - administration & dosage; Quinolones - chemical synthesis; Quinolones - chemistry; Quinolones - pharmacology; Quinolones - therapeutic use; Rats; Rats, Wistar; Structure-Activity Relationship; structure-activity relationships; X-ray diffraction
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2011.06.059

Synthesis, inhibition of dipeptidyl peptidase IV (DPP-4) inhibitory activity of new isoquinolone (35a) are described. 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.