Brodney M.
* et al. Pfizer, Inc., Cambridge and Groton, USA
Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant,
β-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation.
J. Med. Chem. 2018;
61: 4476-4504
Key words
PF-06751979 - BACE1 inhibitors - intramolecular dipolar cycloaddition - nitrones -
quaternary stereocenters - Buchwald–Hartwig amination
Significance
PF-06751979 is a potent brain penetrant β-site amyloid precursor protein cleaving
enzyme 1 (BACE1) inhibitor that is of interest for the treatment of Alzheimer's disease.
It displays broad selectivity over related aspartyl proteases including BACE2 and
cathepsin D. A potential liability of BACE2 inhibition is depigmentation.
Comment
In the key step, the chiral quaternary center in D was constructed via diastereoselective addition of the metallated thiazole C to the convex face of the bicyclic isoxazoline B. The direct conversion of bromothiazole I to N (61%, 0.11 mmol scale) via a Buchwald–Hartwig coupling with 5-(difluoromethoxy)picolinamide
is also reported. See also the synthesis of LY2886721: Org. Process Res. Dev. 2015, 19, 1214.
