Design and synthesis of statine-containing BACE inhibitors.
Utilizing structure-based techniques and solid-phase synthesis, statine-based tetrapeptide BACE inhibitors were designed and synthesized using a heptapeptide BACE transition-state mimetic, 1, as the starting point. Structure-activity relationship studies at the P(3), P(2), and P(2)' positions as well as the N-terminal capping group on scaffold 5 led to the discovery of potent inhibitors 27, 32, and 34 (IC(50) <100 nM). In addition, computational analysis and the X-ray structure of BACE-inhibitor 38 are discussed.
Hu
Jingdan
J
Eli Lilly and Company, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA. hu_jingdan@lilly.com
Cwi
Cynthia L
CL
Smiley
David L
DL
Timm
David
D
Erickson
Jon A
JA
McGee
James E
JE
Yang
Hsiu-Chiung
HC
Mendel
David
D
May
Patrick C
PC
Shapiro
Mike
M
McCarthy
James R
JR
D000544:Alzheimer Disease / Q000201:enzymology; D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry / Q000494:pharmacology*; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D015195:Drug Design; D010450:Endopeptidases; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000596:Amino Acids; D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509284:BACE2 protein, human; C509280:BACE1 protein, human; C013165:statine