Novel pyrrolyl 2-aminopyridines as potent and selective human beta-secretase (BACE1) inhibitors.
The proteolytic enzyme beta-secretase (BACE1) plays a central role in the synthesis of the pathogenic beta-amyloid in Alzheimer's disease. Recently, we reported small molecule acylguanidines as potent BACE1 inhibitors. However, many of these acylguanidines have a high polar surface area (e.g. as measured by the topological polar surface area or TPSA), which is unfavorable for crossing the blood-brain barrier. Herein, we describe the identification of the 2-aminopyridine moiety as a bioisosteric replacement of the acylguanidine moiety, which resulted in inhibitors with lower TPSA values and superior brain penetration. X-ray crystallographic studies indicated that the 2-aminopyridine moiety interacts directly with the catalytic aspartic acids Asp32 and Asp228 via a hydrogen-bonding network.
Malamas
Michael S
MS
Department of Chemical Sciences, Wyeth, CN 8000, Princeton, NJ 08543-8000, USA. malamas.michael@gmail.com
Barnes
Keith
K
Hui
Yu
Y
Johnson
Matthew
M
Lovering
Frank
F
Condon
Jeff
J
Fobare
William
W
Solvibile
William
W
Turner
Jim
J
Hu
Yun
Y
Manas
Eric S
ES
Fan
Kristi
K
Olland
Andrea
A
Chopra
Rajiv
R
Bard
Jonathan
J
Pangalos
Menelas N
MN
Reinhart
Peter
P
Robichaud
Albert J
AJ
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000201:enzymology; D000631:Aminopyridines / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D001921:Brain / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000631:Aminopyridines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C032439:alpha-aminopyridine