Discovery of a Highly Potent, Selective, and Bioavailable Soluble Epoxide Hydrolase Inhibitor with Excellent Ex Vivo Target Engagement

4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibit...

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Veröffentlicht in:	Journal of medicinal chemistry 2009-08, Vol.52 (16), p.5009-5012
Hauptverfasser:	Shen, Hong C, Ding, Fa-Xiang, Wang, Siyi, Deng, Qiaolin, Zhang, Xiaoping, Chen, Yuli, Zhou, Gaochao, Xu, Suoyu, Chen, Hsuan-shen, Tong, Xinchun, Tong, Vincent, Mitra, Kaushik, Kumar, Sanjeev, Tsai, Christine, Stevenson, Andra S, Pai, Lee-Yuh, Alonso-Galicia, Magdalena, Chen, Xiaoli, Soisson, Stephen M, Roy, Sophie, Zhang, Bei, Tata, James R, Berger, Joel P, Colletti, Steven L
Format:	Artikel
Sprache:	eng
Schlagworte:	Animals Antihypertensive agents Biological and medical sciences Biological Availability Cardiovascular system Cell Line Crystallography, X-Ray Cytochrome P-450 Enzyme Inhibitors Cytochrome P-450 Enzyme System - metabolism Eicosanoids - metabolism Epoxide Hydrolases - antagonists & inhibitors Epoxy Compounds - metabolism Humans In Vitro Techniques Ion Channels - antagonists & inhibitors Ion Channels - metabolism Kidney - drug effects Kidney - metabolism Medical sciences Mesenteric Arteries - drug effects Mesenteric Arteries - physiology Models, Molecular Molecular Conformation Muscle Relaxation Muscle, Smooth, Vascular - drug effects Muscle, Smooth, Vascular - physiology Pharmacology. Drug treatments Piperidines - chemical synthesis Piperidines - pharmacokinetics Piperidines - pharmacology Rats Rats, Inbred SHR Solubility Stereoisomerism Structure-Activity Relationship Urea - analogs & derivatives Urea - chemical synthesis Urea - pharmacokinetics Urea - pharmacology Vasodilator agents. Cerebral vasodilators
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Zusammenfassung:	4-Substituted piperidine-derived trisubstituted ureas are reported as highly potent and selective inhibitors for sEH. The SAR outlines approaches to improve activity against sEH and reduce ion channel and CYP liability. With minimal off-target activity and a good PK profile, the benchmark 2d exhibited remarkable in vitro and ex vivo target engagement. The eutomer entA- 2d also elicited vasodilation effect in rat mesenteric artery.
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm900725r