Macrocyclic BACE inhibitors: Optimization of a micromolar hit to nanomolar leads.
We have identified macrocyclic inhibitors of the aspartic protease BACE, implicated in the etiology of Alzheimer's disease. An X-ray structure of screening hit 1 in the BACE active site revealed a hairpin conformation suggesting that constrained macrocyclic derivatives may also bind there. Several of the analogs we prepared were >100x more potent than 1, such as 7 (5 nM K(i)).
Huang
Yifang
Y
Research and Early Development, Johnson & Johnson Pharmaceutical Research & Development, LLC, Spring House, PA 19477-0776, USA.
Strobel
Eric D
ED
Ho
Chih Y
CY
Reynolds
Charles H
CH
Conway
Kelly A
KA
Piesvaux
Jennifer A
JA
Brenneman
Douglas E
DE
Yohrling
George J
GJ
Moore Arnold
H
H
Rosenthal
Daniel
D
Alexander
Richard S
RS
Tounge
Brett A
BA
Mercken
Marc
M
Vandermeeren
Marc
M
Parker
Michael H
MH
Reitz
Allen B
AB
Baxter
Ellen W
EW
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001665:Binding Sites; D003198:Computer Simulation; D006801:Humans; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011480:Protease Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011799:Quinazolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D047028:Macrocyclic Compounds; D011480:Protease Inhibitors; D011799:Quinazolines; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human