Machauer, Rainer, Lueoend, Rainer Martin, Hurth, Konstanze, Veenstra, Siem, Rueeger, Heinrich, Voegtle, Markus, Tintelnot-Blomley, Marina, Rondeau, Jean-Michel, Jacobson, Laura, Laue, Grit, Beltz, Karen and Neumann, Ulf (2021) Discovery of Umibecestat (CNP520): A Potent, Selective and Efficacious β-Secretase (BACE1) Inhibitor for the Prevention of Alzheimer’s Disease. Journal of Medicinal Chemistry, 64 (20). pp. 15262-15279. ISSN 0022-26231520-4804

Abstract

Starting from lead compound 6, 5-amino-1,4-oxazine BACE1 inhibitors were optimised in order to improve potency, brain penetration and metabolic stability. Insertion of a Me and a CF3 group at the 6-position of the 5-amino-1,4-oxazine, led to 8 (NB-360) an inhibitor with a pKa of 7.1, a very low P-gp efflux ratio and excellent pharmacological profile enabling high CNS penetration and exposure. Fur color changes observed with NB-360 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-((3R,6R)-5-amino-3,6-dimethyl-6-trifluoromethyl-3,6-dihydro-2H-[1,4]oxazin-3-yl)-5-fluoro-pyridin-2-yl]amide 15 (CNP520, umibecestat), an inhibitor with superior BACE1/BACE2 selectivity and pharmacokinetics. CNP520 reduced significantly Aβ levels in mice and rats in acute and chronic treatment regimen without any side effects and thus qualified for AD prevention studies in the clinic.

Item Type:	Article
Keywords:	Alzheimer’s disease, BACE1, Beta-site APP-cleaving enzyme, β-Secretase, 5-amino-1,4-oxazine BACE1 inhibitor, pKa, P-gp, BACE2, PMEL17
Date Deposited:	30 Nov 2021 00:45
Last Modified:	30 Nov 2021 00:45
URI:	https://oak.novartis.com/id/eprint/45277