Discovery of 3,3-disubstituted piperidine-derived trisubstituted ureas as highly potent soluble epoxide hydrolase inhibitors.
3,3-Disubstituted piperidine-derived trisubstituted urea entA-2b was discovered as a highly potent and selective soluble epoxide hydrolase (sEH) inhibitor. Despite the good compound oral exposure, excellent sEH inhibition in whole blood, and remarkable selectivity, compound entA-2b failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This observation further challenges the premise that sEH inhibition can provide a viable approach to the treatment of hypertensive patients.
Shen
Hong C
HC
Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA. hong_shen@merck.com
Ding
Fa-Xiang
FX
Deng
Qiaolin
Q
Xu
Suoyu
S
Chen
Hsuan-Shen
HS
Tong
Xinchun
X
Tong
Vincent
V
Zhang
Xiaoping
X
Chen
Yuli
Y
Zhou
Gaochao
G
Pai
Lee-Yuh
LY
Alonso-Galicia
Magdalena
M
Zhang
Bei
B
Roy
Sophie
S
Tata
James R
JR
Berger
Joel P
JP
Colletti
Steven L
SL
D015126:8,11,14-Eicosatrienoic Acid / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008958:Models, Molecular; D010880:Piperidines / Q000737:chemistry*; D011485:Protein Binding; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000627:therapeutic use
C107016:14,15-dihydroxyeicosatrienoic acid; D010880:Piperidines; C032727:piperidine; D014508:Urea; D004851:Epoxide Hydrolases; D015126:8,11,14-Eicosatrienoic Acid