title: 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.
abstract: 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 IC50 values of 0.78, 0.49, 0.14 microM, respectively. In addition, the compound (10 microM) 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.
authors.affiliation: Medicinal Science Division, Korea Research Institute of Chemical Technology, Jang-Dong 100, Yusung Gu, TaeJon, 305-343, South Korea.
authors.forename: Kwang-Rok
authors.initials: KR
authors.lastname: Kim
authors.forename: Sang-Dal
authors.initials: SD
authors.lastname: Rhee
authors.forename: Hee Youn
authors.initials: HY
authors.lastname: Kim
authors.forename: Won Hoon
authors.initials: WH
authors.lastname: Jung
authors.forename: Sung-Don
authors.initials: SD
authors.lastname: Yang
authors.forename: Sung Soo
authors.initials: SS
authors.lastname: Kim
authors.forename: Jin Hee
authors.initials: JH
authors.lastname: Ahn
authors.forename: Hyae Gyeong
authors.initials: HG
authors.lastname: Cheon
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D018938:Caco-2 Cells; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000517:prevention & control; D018819:Dipeptidyl Peptidase 4 / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005934:Glucagon / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000097:blood; D007700:Kinetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009539:Nicotinic Acids / Q000494:pharmacology*; D009570:Nitriles / Q000494:pharmacology*; D010446:Peptide Fragments / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D010447:Peptide Hydrolases / Q000378:metabolism; D011498:Protein Precursors / Q000097:blood / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013552:Swine
chemical_list: D001786:Blood Glucose; D004791:Enzyme Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; C503941:KR-62436; D009539:Nicotinic Acids; D009570:Nitriles; D010446:Peptide Fragments; D011498:Protein Precursors; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D010447:Peptide Hydrolases; D018819:Dipeptidyl Peptidase 4