Discovery of 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted urea derivatives as highly potent soluble epoxide hydrolase inhibitors and orally active drug candidates for treating of chronic kidney diseases |
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| Affiliation: | 1. Toray Industries, Inc., Pharmaceutical Research Laboratories, 6-10-1 Tebiro, Kamakura, Kanagawa 248-8555, Japan;2. Department of Chemistry, Graduate School of Pure and Applied Sciences, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki 305-8571, Japan;1. Department of Chemistry, Tarbiat Modares University, PO Box 14115-175, Tehran, Iran;2. Department of Chemistry, Zhejiang University, Hangzhou 310027, PR China;1. Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China;2. School of Pharmaceutical Sciences, Southern Medical University, Guangzhou 510515, China;3. Natural Products Research Laboratories, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA;4. Beijing Institute of Radiation Medicine, Beijing 100850, China;5. Chinese Medicine Research and Development Center, China Medical University and Hospital, Taichung, Taiwan;1. University Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie Thérapeutique, Equipe Labellisée Ligue Contre Le Cancer, LabEx LERMIT, Faculté de Pharmacie, 5 rue J.-B. Clément, Châtenay-Malabry F-92296, France;2. Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, Dr. J. Bignon, Dr. J. Dubois, avenue de la Terrasse, F-91198 Gif sur Yvette, France |
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| Abstract: | We identified 1-oxa-4,9-diazaspiro[5.5]undecane-based trisubstituted ureas as highly potent soluble epoxide hydrolase (sEH) inhibitors and orally active agents for treating chronic kidney diseases. Compound 19 exhibited excellent sEH inhibitory activity and bioavailability. When administered orally at 30 mg/kg, 19 lowered serum creatinine in a rat model of anti-glomerular basement membrane glomerulonephritis but 2,8-diazaspiro[4.5]decane-based trisubstituted ureas did not. These results suggest that 19 is an orally active drug candidate for treating chronic kidney diseases. |
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| Keywords: | sEH inhibitor Anti-GBM glomerulonephritis rat model Spirocyclic diamine Urea Chronic kidney diseases |
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