Discovery of novel benzoxazinones as potent and orally active long chain fatty acid elongase 6 inhibitors.
Basic Information
ID: ALA1154682
Journal: J Med Chem
Title: Discovery of novel benzoxazinones as potent and orally active long chain fatty acid elongase 6 inhibitors.
Authors: Mizutani T, Ishikawa S, Nagase T, Takahashi H, Fujimura T, Sasaki T, Nagumo A, Shimamura K, Miyamoto Y, Kitazawa H, Kanesaka M, Yoshimoto R, Aragane K, Tokita S, Sato N.
Abstract: A series of benzoxazinones was synthesized and evaluated as novel long chain fatty acid elongase 6 (ELOVL6) inhibitors. Exploration of the SAR of the UHTS lead 1a led to the identification of (S)-1y that possesses a unique chiral quarternary center and a pyrazole ring as critical pharmacophore elements. Compound (S)-1y showed potent and selective inhibitory activity toward human ELOVL6 while displaying potent inhibitory activity toward both mouse ELOVL3 and 6 enzymes. Compound (S)-1y showed acceptable pharmacokinetic profiles after oral dosing in mice. Furthermore, (S)-1y significantly suppressed the elongation of target fatty acids in mouse liver at 30 mg/kg oral dosing.
CiteXplore: 19883081
DOI: 10.1021/jm900915x
Patent ID: ┄