Phe*-Ala-based pentapeptide mimetics are BACE inhibitors: P2 and P3 SAR.
We describe herein the syntheses and evaluation of a series of C-termini pyridyl containing Phe*-Ala-based BACE inhibitors (5-19). In conjunction with four fixed residues at the P1 (Phe), P1' (Ala), P2' (Val), and P2' cap (Pyr.), rather detailed SAR modifications at P2 and P3 positions were pursued. The promising inhibitors emerging from this SAR investigation, 12 and 17 demonstrated very good enzyme potency (IC(50)=45 nM) and cellular activity (IC(50)=0.4 microM).
Lamar
Jason
J
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Hu
Jingdan
J
Bueno
Ana Belen
AB
Yang
Hsiu-Chiung
HC
Guo
Deqi
D
Copp
James D
JD
McGee
James
J
Gitter
Bruce
B
Timm
David
D
May
Patrick
P
McCarthy
James
J
Chen
Shu-Hui
SH
D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; D002460:Cell Line; D004151:Dipeptides / Q000138:chemical synthesis* / Q000633:toxicity; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D018716:Molecular Mimicry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000633:toxicity; D013329:Structure-Activity Relationship
D004151:Dipeptides; D011480:Protease Inhibitors; C039552:phenylalanylalanine; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human