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Synfacts 2018; 14(08): 0775
DOI: 10.1055/s-0037-1609873
Synthesis of Natural Products and Potential Drugs
© Georg Thieme Verlag Stuttgart · New York

Synthesis of PF-06751979

Contributor(s):
Philip Kocienski
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
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Further Information

Publication History

Publication Date:
18 July 2018 (online)

 
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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.


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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.


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