KR-62436, 6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitrile, is a novel dipeptidyl peptidase-IV (DPP-IV) inhibitor with anti-hyperglycemic activity

• Published in: European journal of pharmacology 2005-07, Vol.518 (1), p.63-70
• Main Authors: Kim, Kwang-Rok, Rhee, Sang-Dal, Hee Youn Kim, Won Hoon Jung, Yang, Sung-Don, Sung Soo Kim, Jin Hee Ahn, Hyae Gyeong Cheon
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blood Glucose - metabolism; Caco-2 Cells; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - prevention & control; Dipeptidyl Peptidase 4 - blood; Dipeptidyl Peptidase 4 - chemistry; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl peptidase-IV; Dose-Response Relationship, Drug; Enzyme Inhibitors - pharmacology; Glucagon - blood; Glucagon - chemistry; Glucagon - metabolism; Glucagon-Like Peptide 1; Glucose Tolerance Test; Humans; Hypoglycemic Agents - pharmacology; Hypoglycemic Agents - therapeutic use; Insulin; Insulin - blood; Kinetics; Male; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Obese; Nicotinic Acids - pharmacology; Nitriles - pharmacology; Ob/ ob mice; Oral glucose tolerance test; Peptide Fragments - blood; Peptide Fragments - chemistry; Peptide Fragments - metabolism; Peptide Hydrolases - metabolism; Pharmacology. Drug treatments; Protein Precursors - blood; Protein Precursors - chemistry; Protein Precursors - metabolism; Rats; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Swine
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2005.05.030

Dipeptidyl peptidase-IV (DPP-IV) is involved in the inactivation of glucagon-like peptide-1 (GLP-1), a potent insulinotropic peptide. Thus, DPP-IV inhibition can be an effective approach to treat type 2 diabetes mellitus by potentiating insulin secretion. This study describes the biological effects of a new DPP-IV inhibitor, KR-62436 (6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitrile) in vitro and in vivo. KR-62436 inhibited rat plasma DPP-IV, porcine kidney DPP-IV as well as human DPP-IV (Caco-2) with IC 50 values of 0.78, 0.49, 0.14 μM, respectively. In addition, the compound (10 μM) almost completely inhibited DPP-IV-mediated degradation of GLP-1 in vitro. KR-62436 inhibited the enzyme in a competitive manner, and exhibited selectivity against several proteases including proline-specific proteases. In vivo efficacy of the compound was examined by using normal C57BL/6J mice and ob/ ob mice, a type 2 diabetes animal model. Administration of KR-62436 to C57BL/6J mice either orally or subcutaneously resulted in the suppression of plasma DPP-IV activity, increase in intact GLP-1 and insulin levels in plasma. Furthermore, the plasma glucose concentrations during oral glucose tolerance test (OGTT) were reduced upon oral administration of KR-62436. This study demonstrates that KR-62436 could be a good lead compound for further development as a new anti-diabetic agent.