title: Discovery of an orally efficaceous 4-phenoxypyrrolidine-based BACE-1 inhibitor.
abstract: Based on a lead compound identified from the patent literature, we developed patentably novel BACE-1 inhibitors by introducing a cyclic amine scaffold as embodied by 1a and 1b. Extensive SAR studies assessed a variety of isophthalamide replacements including substituted pyrrolidinones and ultimately led to the identification of 11. Due to its favorable overall profile, 11 has been extensively profiled in various in vivo settings.
authors.affiliation: Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. ulrich.iserloh@spcorp.com
authors.forename: U
authors.initials: U
authors.lastname: Iserloh
authors.forename: J
authors.initials: J
authors.lastname: Pan
authors.forename: A W
authors.initials: AW
authors.lastname: Stamford
authors.forename: M E
authors.initials: ME
authors.lastname: Kennedy
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.forename: L
authors.initials: L
authors.lastname: Zhang
authors.forename: E M
authors.initials: EM
authors.lastname: Parker
authors.forename: N A
authors.initials: NA
authors.lastname: McHugh
authors.forename: L
authors.initials: L
authors.lastname: Favreau
authors.forename: C
authors.initials: C
authors.lastname: Strickland
authors.forename: J
authors.initials: J
authors.lastname: Voigt
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D010636:Phenols / Q000737:chemistry; D011480:Protease Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D011759:Pyrrolidines / Q000737:chemistry* / Q000493:pharmacokinetics* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D010636:Phenols; D011480:Protease Inhibitors; D011759:Pyrrolidines; C042329:phenoxy radical; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; C509282:Bace1 protein, mouse