Pyrrolidines as conformationally constrained diaminopropanes: A versatile scaffold for potent inhibitors of BACE-1

MEDI 296

Jason M. Guernon, jason.guernon@bms.com1, Lorin A. Thompson III1, John E. Macor1, Andrew J. Tebben2, Andrew Good2, Catherine R. Burton3, Donna M. Barten3, Jovita Marcinkeviciene4, Jeremy H. Toyn3, Charlie Albright3, Jodi K. Muckelbauer5, Daniel Camac5, Tatyana Zvyaga6, James Grace7, Kimberly Lentz7, and Kenneth M. Boy, boyk@bms.com1. (1) Neuroscience Chemistry, Bristol-Myers Squibb, 5 Research Parkway, Wallingford, CT 06492, (2) Computer Assisted Drug Design, Bristol-Myers Squibb, (3) Neuroscience Biology, Bristol-Myers Squibb, (4) Chemical Enzymology, Bristol-Myers Squibb, (5) X-Ray Crystallography, Bristol-Myers Squibb, (6) Lead Profiling, Bristol-Myers Squibb, (7) MAP Discovery, Bristol-Myers Squibb
The production of the amyloidogenic A-beta 1-42 protein fragment from Amyloid precursor protein (APP) is postulated to initiate the pathology characteristic of Alzheimer's disease. Beta-secretase (BACE) and Gamma-secretase are responsible for the liberation of A-beta 1-42, so inhibition of these enzymes would be of potential therapeutic benefit. Previously reported Gamma-lactam-diaminopropanes were potent in-vitro inhibitors of BACE. A conformationally restricted pyrrolidine template was successfully incorporated. Crucial properties including CYP profile, PGP efflux, and selectivity versus other aspartyl proteases were attenuated by functionalization of the 4- and 5-positions of the pyrrolidine. The rationale for these compounds will be discussed as well as their synthesis and properties.
 

Poster Session
7:00 PM-9:00 PM, Wednesday, August 22, 2007 BCEC -- Exhibit Hall - B2, Poster

Division of Medicinal Chemistry

The 234th ACS National Meeting, Boston, MA, August 19-23, 2007