A strategy of employing aminoheterocycles as amide mimics to identify novel, potent and bioavailable soluble epoxide hydrolase inhibitors.
Distinct from previously reported urea and amide inhibitors of soluble epoxide hydrolase (sEH), a novel class of inhibitors were rationally designed based on the X-ray structure of this enzyme and known amide inhibitors. The structure-activity relationship (SAR) study was focused on improving the sEH inhibitory activity. Aminobenzisoxazoles emerged to be the optimal series, of which a potent human sEH inhibitor 7t was identified with a good pharmacokinetics (PK) profile. The strategy of employing aminoheterocycles as amide replacements may represent a general approach to develop mimics of known hydrolase or protease inhibitors containing an amide moiety.
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
Tong
Xinchun
X
Zhang
Xiaoping
X
Chen
Yuli
Y
Zhou
Gaochao
G
Pai
Lee-Yuh
LY
Alonso-Galicia
Magdalena
M
Roy
Sophie
S
Zhang
Bei
B
Tata
James R
JR
Berger
Joel P
JP
Colletti
Steven L
SL
D000577:Amides / Q000737:chemistry*; D000814:Aniline Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006574:Heterocyclic Compounds, 2-Ring / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D011485:Protein Binding; D051381:Rats; D013329:Structure-Activity Relationship
D000577:Amides; D000814:Aniline Compounds; D004791:Enzyme Inhibitors; D006574:Heterocyclic Compounds, 2-Ring; D007555:Isoxazoles; D004851:Epoxide Hydrolases