Inhibitors of Abeta production: solid-phase synthesis and SAR of alpha-hydroxycarbonyl derivatives.
Inhibitors of amyloid-beta (Abeta) protein production have been widely pursued as a potential treatment for Alzheimer's disease. Following the identification of a 5 microM screening hit, SAR was initiated using solid-phase synthetic techniques. Two series of alpha-hydroxy esters and ketones which are sub-micromolar inhibitors of Abeta production were identified. The most potent alpha-hydroxyketone identified is approximately 30-fold more potent than the initial lead.
Wallace
Owen B
OB
Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway, Wallingford, CT 06492, USA. owen.wallace@lilly.com
Smith
David W
DW
Deshpande
Milind S
MS
Polson
Craig
C
Felsenstein
Kevin M
KM
D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015195:Drug Design; D004797:Enzyme-Linked Immunosorbent Assay; D004952:Esters / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D013329:Structure-Activity Relationship
D016229:Amyloid beta-Peptides; D004952:Esters; D007202:Indicators and Reagents