Preparation and evaluation of soluble epoxide hydrolase inhibitors with improved physical properties and potencies for treating diabetic neuropathic pain |
| |
| Institution: | 1. Synthia LLC, Davis, CA 95616, United States;2. Department of Entomology and Nematology, One Shields Ave, University of California-Davis, Davis, CA 95616, United States;3. EicOsis Human Health, 140 B Street, Suite 5, Number 346, Davis, CA 95616, United States;1. College of Pharmacy, College (Institute) of Integrative Medicine, The National & Local Joint Engineering Research Center for Drug Development of Neurodegenerative Disease, Dalian Medical University, Dalian, China;2. School of Life Science, Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, Liaoning Normal University, Dalian, China;3. School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China;4. Analysis Center of College of Science & Technology, Hebei Agricultural University, Cangzhou, Hebei, China;5. Department of Entomology and Nematology, UC Davis Comprehensive Cancer Center, University of California, Davis, CA, USA;1. Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA 95616, USA;2. Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (branch) Volgograd State Technical University, Volzhsky 404121, Russia;3. Skolkovo Institute of Science and Technology, Skolkovo Innovation Center, Moscow 143026, Russia;4. Department of Chemistry, Lomonosov Moscow State University, Moscow 119991, Russia;5. Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka, Moscow Region 142432, Russia;6. School of Chemistry, Volgograd State Technical University, Volgograd 400131, Russia;1. Pharmaceutical Institute, University of Bonn, An der Immenburg 4, D-53121, Bonn, Germany;2. Institute of Pharmaceutical Chemistry, Goethe-University Frankfurt, Max-von-Laue-Strasse 9, D-60438, Frankfurt Am Main, Germany;1. Department of Pharmacology, Al-Ameen College of Pharmacy, Bangalore, Karnataka, India;2. Department of Entomology and Nematology, and Comprehensive Cancer Center, University of California, Davis, CA, USA;3. Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA |
| |
| Abstract: | Soluble epoxide hydrolase (sEH), a novel therapeutic target for neuropathic pain, is a largely cytosolic enzyme that degrades epoxy-fatty acids (EpFAs), an important class of lipid signaling molecules. Many inhibitors of sEH have been reported, and to date, the 1,3-disubstituted urea has the highest affinity reported for the sEH among the central pharmacophores evaluated. An earlier somewhat water soluble sEH inhibitor taken to the clinic for blood pressure control had mediocre potency (both affinity and kinetics) and a short in vivo half-life. We undertook a study to overcome these difficulties, but the sEH inhibitors carrying a 1,3-disubstituted urea often suffer poor physical properties that hinder their formulation. In this report, we described new strategies to improve the physical properties of sEH inhibitors with a 1,3-disubstituted urea while maintaining their potency and drug-target residence time (a complementary in vitro parameter) against sEH. To our surprise, we identified two structural modifications that substantially improve the potency and physical properties of sEH inhibitors carrying a 1,3-disubstituted urea pharmacophore. Such improvements will greatly facilitate the movement of sEH inhibitors to the clinic. |
| |
| Keywords: | Soluble epoxide hydrolase Inhibitor Neuropathic pain Physical properties Drug target residence time Drug design |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
