BACE-1 inhibition by a series of psi[CH2NH] reduced amide isosteres.
A series of beta-site amyloid precursor protein cleaving enzyme (BACE-1) inhibitors containing a psi(CH2NH) reduced amide bond were synthesized. Incorporation of this reduced amide isostere as a non-cleavable peptide surrogate afforded inhibitors possessing low nanomolar potencies in both an enzymatic and cell-based assay.
Coburn
Craig A
CA
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA. craig_coburn@merck.com
Stachel
Shawn J
SJ
Jones
Kristen G
KG
Steele
Thomas G
TG
Rush
Diane M
DM
DiMuzio
Jillian
J
Pietrak
Beth L
BL
Lai
Ming-Tain
MT
Huang
Qian
Q
Lineberger
Janet
J
Jin
Lixia
L
Munshi
Sanjeev
S
Katharine Holloway
M
M
Espeseth
Amy
A
Simon
Adam
A
Hazuda
Daria
D
Graham
Samuel L
SL
Vacca
Joseph P
JP
D000577:Amides / Q000737:chemistry*; D053829:Amyloid Precursor Protein Secretases; D001665:Binding Sites; D010450:Endopeptidases / Q000378:metabolism*; D007118:Immunoassay; D010455:Peptides / Q000737:chemistry; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000577:Amides; D010455:Peptides; D011480:Protease Inhibitors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases