ortho-Substituted azoles as selective and dual inhibitors of VEGF receptors 1 and 2
DOI: 10.1016/j.bmcl.2006.11.087
Title: ortho-Substituted azoles as selective and dual inhibitors of VEGF receptors 1 and 2
Journal Title: Bioorganic & Medicinal Chemistry Letters
Volume: 17
Issue: 5
Publication Date: 1 March 2007
Start Page: 1369
End Page: 1375
Published online: online 2 December 2006
ISSN: 0960-894X
Affiliations:

  • a Small Molecule Drug Discovery, Chemical Diversity, Inc., 11558 Sorrento Valley Road, San Diego, CA 92121, USA

  • b Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Prospect, 117913 Moscow, Russia
  • Abstract: developed a series of novel potent ortho-Substituted azole derivatives active against kinases VEGFR-1 and VEGFR-2. Both specific and dual ATP-competitive inhibitors of VEGFR-2 were identified. Kinase activity and selectivity could be controlled by varying the arylamido substituents at the azole ring. The most specific molecule (17) displayed >10-fold selectivity for VEGFR-2 over VEGFR-1. Compound activities in enzymatic and cell-based assays were in the range of activities for reported clinical and development candidates (IC50 < 100 nM), including Novartis’ PTK787 (Vatalanib)™. High permeability of active compounds across the Caco-2 cell monolayer (>30 × 10−5 cm/min) is indicative of their potential for intestinal absorption upon oral administration.
    Accepted: 30 November 2006
    Received: 16 October 2006
    Revised: 18 November 2006
    Tel: +7 617 551 3302.Copyright ©
    Email: semenovictor@gmail.com

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