Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors.
Spirocyclic secondary amine-derived trisubstituted ureas were identified as highly potent, bioavailable and selective soluble epoxide hydrolase (sEH) inhibitors. Despite good oral exposure and excellent ex vivo target engagement in blood, one such compound, rac-1a, failed to lower blood pressure acutely in spontaneously hypertensive rats (SHRs). This study posed the question as to whether sEH inhibition provides a robust mechanism leading to a significant antihypertensive effect.
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
Wang
Siyi
S
Xu
Suoyu
S
Chen
Hsuan-shen
HS
Tong
Xinchun
X
Tong
Vincent
V
Mitra
Kaushik
K
Kumar
Sanjeev
S
Zhang
Xiaoping
X
Chen
Yuli
Y
Zhou
Gaochao
G
Pai
Lee-Yuh
LY
Alonso-Galicia
Magdalena
M
Chen
Xiaoli
X
Zhang
Bei
B
Tata
James R
JR
Berger
Joel P
JP
Colletti
Steven L
SL
D000588:Amines / Q000737:chemistry*; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D002460:Cell Line; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D051381:Rats; D011918:Rats, Inbred SHR; D013141:Spiro Compounds / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014508:Urea / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics
D000588:Amines; D000959:Antihypertensive Agents; D004791:Enzyme Inhibitors; D013141:Spiro Compounds; D014508:Urea; D004851:Epoxide Hydrolases