Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 20, Pages 15262-15279Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c01300
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Through optimization of BACE1 inhibitors, the study identified CNP520 (umibecestat), a compound with superior selectivity and pharmacokinetic properties that significantly reduced Aβ levels in mice and rats without any side effects, making it a potential candidate for Alzheimer's disease prevention in clinical studies.
After identification of lead compound 6, 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 8 (NB-360), an inhibitor with a pK(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 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 A beta 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.
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