Design, Synthesis, and Evaluation of Orally Active Benzimidazoles and Benzoxazoles as Vascular Endothelial Growth Factor-2 Receptor Tyrosine Kinase Inhibitors
Michele PotashmanDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799James BreadyDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Angela CoxonDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Thomas M. DeMelfiDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Lucian DiPietroDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Nicholas DoerrDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Daniel ElbaumDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Juan EstradaDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Paul GallantDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Julie GermainDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Yan GuDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Jean-Christophe HarmangeDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Stephen A. KaufmanDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Rick A. KendallDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Joseph L. KimDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Gondi KumarDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Alexander LongDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Seshadri NeervannanDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Vinod F. PatelDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Anthony PolverinoDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Paul RoseDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Simon van der PlasDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Douglas A. WhittingtonDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Roger ZanonDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799Huilin ZhaoDepartment of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, Massachusetts 02139, and Oncology Research, Pharmaceutics, and Pharmacokinetic Drug Metabolism, Amgen Inc., One Amgen Center Drive, Thousand Oaks, California 91320-1799
2007en
ABI
Аннотация
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 (ED(50) = 16.3 mg/kg).
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