Discovery of Umibecestat (CNP520): A Potent, Selective, and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer’s Disease

Abstract

After identification of lead compound <b>6</b>, 5-amino-1,4-oxazine BACE1 inhibitors were optimized in order to improve potency, brain penetration, and metabolic stability. Insertion of a methyl and a trifluoromethyl group at the 6-position of the 5-amino-1,4-oxazine led to <b>8</b> (<b>NB-360</b>), an inhibitor with a p<i>K</i>_a of 7.1, a very low P-glycoprotein efflux ratio, and excellent pharmacological profile, enabling high central nervous system penetration and exposure. Fur color changes observed with <b>NB-360</b> in efficacy studies in preclinical animal models triggered further optimization of the series. Herein, we describe the steps leading to the discovery of 3-chloro-5-trifluoromethyl-pyridine-2-carboxylic acid [6-((3<i>R</i>,6<i>R</i>)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2<i>H</i>-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide <b>15</b> (<b>CNP520</b>, <b>umibecestat</b>), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. <b>CNP520</b> reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimens without any side effects and thus qualified for Alzheimer's disease prevention studies in the clinic.