Discovery of Novel Benzoxazinones as Potent and Orally Active Long Chain Fatty Acid Elongase 6 Inhibitors

摘要: A series of benzoxazinones was synthesized and evaluated as novel long chain fatty acid elongase 6 (ELOVL6) inhibitors. Exploration the SAR UHTS lead 1a led to identification (S)-1y that possesses a unique chiral quarternary center pyrazole ring critical pharmacophore elements. Compound showed potent selective inhibitory activity toward human ELOVL6 while displaying both mouse ELOVL3 enzymes. acceptable pharmacokinetic profiles after oral dosing in mice. Furthermore, significantly suppressed elongation target acids liver at 30 mg/kg dosing.