Discovery of an orally efficaceous 4-phenoxypyrrolidine-based BACE-1 inhibitor.
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.
Iserloh
U
U
Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. ulrich.iserloh@spcorp.com
Pan
J
J
Stamford
A W
AW
Kennedy
M E
ME
Zhang
Q
Q
Zhang
L
L
Parker
E M
EM
McHugh
N A
NA
Favreau
L
L
Strickland
C
C
Voigt
J
J
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
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