Synthesis and structure-activity relationship studies of 1,3-disubstituted 2-propanols as BACE-1 inhibitors.
A library of 1,3-disubstituted 2-propanols was synthesized and evaluated as low molecular weight probes for β-secretase inhibition. By screening a library of 121 1,3-disubstituted 2-propanol derivatives, we identified few compounds inhibiting the enzyme at low micromolar concentrations. The initial hits were optimized to yield a potent BACE-1 inhibitor exhibiting an IC(50) constant in the nanomolar range. Exploration of the pharmacological properties revealed that these small molecular inhibitors possessed a high selectivity over cathepsin D and desirable physicochemical properties beneficial to cross the blood-brain barrier.
Department of Chemistry, University of South Florida, CHE 205, 4202 E. Fowler Ave, Tampa, FL 33620, USA.
Arun Babu
AB
Kumar
Jordan Micheal
JM
Anderson
Anthony Lester
AL
Melendez
Roman
R
Manetsch
D019840:2-Propanol / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D001812:Blood-Brain Barrier / Q000378:metabolism; D002402:Cathepsin D / Q000037:antagonists & inhibitors; D055598:Chemical Phenomena; D015394:Molecular Structure; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology; D013329:Structure-Activity Relationship
D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002402:Cathepsin D; D019840:2-Propanol