P3 cap modified Phe*-Ala series BACE inhibitors.
With the aim of reducing molecular weight and adjusting log D value of BACE inhibitors to more favorable range for BBB penetration and better bioavailability, we synthesized and evaluated several series of P3 cap modified BACE inhibitors obtained via replacement of the P3NHBoc moiety as seen in 3 with other polar functional groups such as amino, hydroxyl and fluorine. Several promising inhibitors emerging from this P3 cap SAR study (e.g., 15 and 19) demonstrated good enzyme inhibitory potencies (BACE-1 IC(50) <50 nM) and whole cell activities (IC(50) approximately 1 microM).
Chen
Shu-Hui
SH
Lilly Research Laboratories, Discovery Chemistry Division and Technology, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA. chen_shu-hui@lilly.com
Lamar
Jason
J
Guo
Deqi
D
Kohn
Todd
T
Yang
Hsiu-Chiung
HC
McGee
James
J
Timm
David
D
Erickson
Jon
J
Yip
Yvonne
Y
May
Patrick
P
McCarthy
James
J
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D011480:Protease Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
D004151:Dipeptides; D011480:Protease Inhibitors; C039552:phenylalanylalanine; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human