Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent, selective and bioavailable soluble epoxide hydrolase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 19; no. 13; pp. 3398 - 3404
• Main Authors: Shen, Hong C., Ding, Fa-Xiang, Wang, Siyi, Xu, Suoyu, Chen, Hsuan-shen, Tong, Xinchun, Tong, Vincent, Mitra, Kaushik, Kumar, Sanjeev, Zhang, Xiaoping, Chen, Yuli, Zhou, Gaochao, Pai, Lee-Yuh, Alonso-Galicia, Magdalena, Chen, Xiaoli, Zhang, Bei, Tata, James R., Berger, Joel P., Colletti, Steven L.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01.07.2009; Elsevier
• Subjects: Amines - chemistry; Animals; Antihypertensive agents; Antihypertensive Agents - chemical synthesis; Antihypertensive Agents - chemistry; Antihypertensive Agents - pharmacokinetics; Biological and medical sciences; Cardiovascular system; Cell Line; Drug Discovery; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacokinetics; Epoxide Hydrolases - antagonists & inhibitors; Epoxide Hydrolases - metabolism; Humans; Medical sciences; Pharmacology. Drug treatments; Rats; Rats, Inbred SHR; sEH; Soluble epoxide hydrolase; Spiro Compounds - chemistry; Spirocyclic secondary amines; Spontaneously hypertensive rats; Structure-Activity Relationship; Tertiary ureas; Urea - analogs & derivatives; Urea - chemical synthesis; Urea - pharmacokinetics; Spirocyclic secondary amines; Spontaneously hypertensive rats; Soluble epoxide hydrolase; Tertiary ureas; sEH; Cyclopropane derivatives; Rat; Cardiovascular disease; Selectivity; Ureas; Chemical synthesis; Secondary amine; Oxygen nitrogen heterocycle; Hypertension; Enzyme; Rodentia; Oral administration; Bioavailability; In vitro; Spiran; In vivo; Vertebrata; Mammalia; Animal; Ether hydrolases; Hydrolases; Inhibitor; Pharmacokinetics
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2009.05.036

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. 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.