title: Design, synthesis, and evaluation of novel VEGFR2 kinase inhibitors: discovery of [1,2,4]triazolo[1,5-a]pyridine derivatives with slow dissociation kinetics.
abstract: For the purpose of discovering novel type-II inhibitors of vascular endothelial growth factor receptor 2 (VEGFR2) kinase, we designed and synthesized 5,6-fused heterocyclic compounds bearing a anilide group. A co-crystal structure analysis of imidazo[1,2-b]pyridazine derivative 2 with VEGFR2 revealed that the N1-nitrogen of imidazo[1,2-b]pyridazine core interacts with the backbone NH group of Cys919. To retain this essential interaction, we designed a series of imidazo[1,2-a]pyridine, [1,2,4]triazolo[1,5-a]pyridine, thiazolo[5,4-b]pyridine, and 1,3-benzothiazole derivatives maintaining a ring nitrogen as hydrogen bond acceptor (HBA) at the corresponding position. All compounds thus designed displayed strong inhibitory activity against VEGFR2 kinase, and the [1,2,4]triazolo[1,5-a]pyridine 13d displayed favorable physicochemical properties. Furthermore, 13d inhibited VEGFR2 kinase with slow dissociation kinetics and also inhibited platelet-derived growth factor receptor (PDGFR) kinases. Oral administration of 13d showed potent anti-tumor efficacy in DU145 and A549 xenograft models in nude mice.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd, 2-26-1 Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan. yuuya.ooguro@takeda.com
authors.forename: Yuya
authors.initials: Y
authors.lastname: Oguro
authors.forename: Douglas R
authors.initials: DR
authors.lastname: Cary
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyamoto
authors.forename: Michiko
authors.initials: M
authors.lastname: Tawada
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Iwata
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Miki
authors.forename: Akira
authors.initials: A
authors.lastname: Hori
authors.forename: Shinichi
authors.initials: S
authors.lastname: Imamura
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D015195:Drug Design; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D008175:Lung Neoplasms / Q000188:drug therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015394:Molecular Structure; D011471:Prostatic Neoplasms / Q000188:drug therapy; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011897:Random Allocation; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D014230:Triazoles; D040301:Vascular Endothelial Growth Factor Receptor-2