Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors.
3-Hydroxyquinolin-2(1H)-one (2) was discovered by high throughput screening in a functional assay to be a potent inhibitor of human DAAO, and its binding affinity was confirmed in a Biacore assay. Cocrystallization of 2 with the human DAAO enzyme defined the binding site and guided the design of new analogues. The SAR, pharmacokinetics, brain exposure, and effects on cerebellum D-serine are described. Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.
Duplantier
Allen J
AJ
Pfizer Global Research and Development, Groton Laboratories, Groton, CT 06340, USA. allen.j.duplantier@pfizer.com
Becker
Stacey L
SL
Bohanon
Michael J
MJ
Borzilleri
Kris A
KA
Chrunyk
Boris A
BA
Downs
James T
JT
Hu
Lain-Yen
LY
El-Kattan
Ayman
A
James
Larry C
LC
Liu
Shenping
S
Lu
Jiemin
J
Maklad
Noha
N
Mansour
Mahmoud N
MN
Mente
Scot
S
Piotrowski
Mary A
MA
Sakya
Subas M
SM
Sheehan
Susan
S
Steyn
Stefanus J
SJ
Strick
Christine A
CA
Williams
Victoria A
VA
Zhang
Lei
L
D000818:Animals; D002531:Cerebellum / Q000378:metabolism; D018360:Crystallography, X-Ray; D003605:D-Amino-Acid Oxidase / Q000037:antagonists & inhibitors*; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D006801:Humans; D006912:Hydroxyquinolines / Q000138:chemical synthesis / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D013329:Structure-Activity Relationship
D006912:Hydroxyquinolines; D012694:Serine; D003605:D-Amino-Acid Oxidase