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Discovery of spirocyclic secondary amine-derived tertiary ureas as highly potent,selective and bioavailable soluble epoxide hydrolase inhibitors |
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| Authors: | Hong C Shen Fa-Xiang Ding Siyi Wang Suoyu Xu Hsuan-shen Chen Xinchun Tong Vincent Tong Kaushik Mitra Sanjeev Kumar Xiaoping Zhang Yuli Chen Gaochao Zhou Lee-Yuh Pai Magdalena Alonso-Galicia Xiaoli Chen Bei Zhang James R Tata Joel P Berger Steven L Colletti |
| Institution: | 1. Department of Medicinal Chemistry, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;2. Department of Drug metabolism, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;3. Department of Metabolic Disorders, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;4. Department of Cardiovascular Diseases, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA;5. Department of Pharmacology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065-0900, USA |
| Abstract: | 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. |
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