1387560-91-9

Upstream product

• 1387560-88-4 methanesulfonic acid 2-azido-1-(2-bromo-5-fluoropyridin-4-yl)-1-methylethyl ester 
• 1387560-85-1 2-(2-bromo-5-fluoropyridin-4-yl)propane-1,2-diol 
• 1387560-84-0 2-bromo-5-fluoro-4-isopropenylpyridine 
• 1387560-83-9 2-(2-bromo-5-fluoropyridin-4-yl)propan-2-ol 
• 41404-58-4 2-bromo-5-fluoropyridine 
• 1387560-90-8 2-bromo-5-fluoro-4-(2-methylaziridin-2-yl)pyridine 
• 1387560-89-5 2-bromo-5-fluoro-4-[2-methyl-1-(2-nitrobenzenesulfonyl)aziridin-2-yl]pyridine 
• 1262860-78-5 (R)-3,3,3-trifluoro-2-hydroxy-2-methylpropionic acid ethyl ester 

Downstream Products

• 1387560-92-0 (R)-2-[2-(2-bromo-5-fluoropyridin-4-yl)-2-(2-nitrobenzenesulfonylamino)propoxy]-3,3,3-trifluoro-2-methylpropionamide 
• 1387560-93-1 N-[1-(2-bromo-5-fluoropyridin-4-yl)-2-((R)-1-cyano-2,2,2-trifluoro-1-methylethoxy)-1-methylethyl]-2-nitrobenzenesulfonamide 

Relevant academic research and scientific papers

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

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 pKa 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 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.

Novel Heterocyclic Derivatives and Their Use in the Treatment of Neurological Disorders

The invention relates to novel heterocyclic compounds of the formula in which all of the variables are as defined in the specification, pharmaceutical compositions thereof, combinations thereof, and their use as medicaments, particularly for the treatment of Alzheimer's Disease or diabetes via inhibition of BACE-1 or BACE-2.