title: Novel pyrrolyl 2-aminopyridines as potent and selective human beta-secretase (BACE1) inhibitors.
abstract: 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.
authors.affiliation: Department of Chemical Sciences, Wyeth, CN 8000, Princeton, NJ 08543-8000, USA. malamas.michael@gmail.com
authors.forename: Michael S
authors.initials: MS
authors.lastname: Malamas
authors.forename: Keith
authors.initials: K
authors.lastname: Barnes
authors.forename: Yu
authors.initials: Y
authors.lastname: Hui
authors.forename: Matthew
authors.initials: M
authors.lastname: Johnson
authors.forename: Frank
authors.initials: F
authors.lastname: Lovering
authors.forename: Jeff
authors.initials: J
authors.lastname: Condon
authors.forename: William
authors.initials: W
authors.lastname: Fobare
authors.forename: William
authors.initials: W
authors.lastname: Solvibile
authors.forename: Jim
authors.initials: J
authors.lastname: Turner
authors.forename: Yun
authors.initials: Y
authors.lastname: Hu
authors.forename: Eric S
authors.initials: ES
authors.lastname: Manas
authors.forename: Kristi
authors.initials: K
authors.lastname: Fan
authors.forename: Andrea
authors.initials: A
authors.lastname: Olland
authors.forename: Rajiv
authors.initials: R
authors.lastname: Chopra
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bard
authors.forename: Menelas N
authors.initials: MN
authors.lastname: Pangalos
authors.forename: Peter
authors.initials: P
authors.lastname: Reinhart
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Robichaud
mesh_terms: 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
chemical_list: D000631:Aminopyridines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C032439:alpha-aminopyridine