347405-65-6Relevant academic research and scientific papers
Design, synthesis, and evaluation of orally active benzimidazoles and benzoxazoles as vascular endothelial growth factor-2 receptor tyrosine kinase inhibitors
Potashman, Michele H.,Bready, James,Coxon, Angela,Demelfi Jr., Thomas M.,DiPietro, Lucian,Doerr, Nicholas,Elbaum, Daniel,Estrada, Juan,Gallant, Paul,Germain, Julie,Gu, Yan,Harmange, Jean-Christophe,Kaufman, Stephen A.,Kendall, Rick,Kim, Joseph L.,Kumar, Gondi N.,Long, Alexander M.,Neervannan, Seshadri,Patel, Vinod F.,Polverino, Anthony,Rose, Paul,Van Der Plas, Simon,Whittington, Douglas,Zanon, Roger,Zhao, Huilin
, p. 4351 - 4373 (2008/02/13)
Inhibition of the VEGF signaling pathway has become a valuable approach in the treatment of cancers. Guided by X-ray crystallography and molecular modeling, a series of 2-aminobenzimidazoles and 2-aminobenzoxazoles were identified as potent inhibitors of VEGFR-2 (KDR) in both enzymatic and HUVEC cellular proliferation assays. In this report we describe the synthesis and structure-activity relationship of a series of 2-aminobenzimidazoles and benzoxazoles, culminating in the identification of benzoxazole 22 as a potent and selective VEGFR-2 inhibitor displaying a good pharmacokinetic profile. Compound 22 demonstrated efficacy in both the murine matrigel model for vascular permeability (79% inhibition observed at 100 mg/kg) and the rat corneal angiogenesis model (ED50 = 16.3 mg/kg).
QUINOLINE OR QUINAZOLINE DERIVATIVES INHIBITING AUTO-PHOSPHORYLATION OF FIBROBLAST GROWTH FACTOR RECEPTORS
-
Page 28, (2008/06/13)
An objective of the present invention is to provide novel compounds which have inhibitory activity against autophosphorylation of an FGF receptor family and, when orally or intraveneously administered, can suppress the growth of cancer cells. The compounds of the present invention are represented by formula (I) or a pharmaceutically acceptable salt or solvate thereof: wherein X represents CH or N; Z represents 0 or S; Q represents NR10, CR11R12, carbonyl, O, S(=O)m, wherein m is 0 to 2, or urea; R1 to R3 each independently represent H, OH, halogen, nitro, amino, alkyl, alkoxy or the like in which the alkyl and alkoxy groups are optionally substituted; R4 represents H; R5 to R8 each independently represent H, halogen, alkyl, or alkoxy; and R9 represents an optionally substituted carbocyclic or heterocyclic group.
Synthesis and structure-activity relationship for new series of 4-phenoxyquinoline derivatives as specific inhibitors of platelet-derived growth factor receptor tyrosine kinase
Kubo, Kazuo,Ohyama, Shin-Ichi,Shimizu, Toshiyuki,Takami, Atsuya,Murooka, Hideko,Nishitoba, Tsuyoshi,Kato, Shinichiro,Yagi, Mikio,Kobayashi, Yoshiko,Iinuma, Noriko,Isoe, Toshiyuki,Nakamura, Kazuhide,Iijima, Hiroshi,Osawa, Tatsushi,Izawa, Toshio
, p. 5117 - 5133 (2007/10/03)
We discovered a new series of 4-phenoxyquinoline derivatives as potent and selective inhibitors of the platelet-derived growth factor receptor (PDGFr) tyrosine kinase. We researched the highly potent and selective inhibitors on the basis of both PDGFr and epidermal growth factor receptor (EGFr) inhibitory activity. First, we found a compound, Ki6783 (1), which inhibited PDGFr autophosphorylation at 0.13 μM, but it did not inhibit EGFr autophosphorylation at 100 μM. After extensive explorations, we found the two desired compounds, Ki6896 (2) and Ki6945 (3), which are substituted by benzoyl and benzamide at the 4-position of the phenoxy group on 4-phenoxyquinoline, respectively. These inhibitory activities were 0.31 and 0.050 μM, respectively, but neither of them inhibited EGFr autophosphorylation at 100 μM. We further investigated the profile of both compounds toward various tyrosine and serine/threonine kinases. The three compounds specifically inhibited PDGFr rather than the other kinases.
