Effects of adamantane alterations on soluble epoxide hydrolase inhibition potency,physical properties and metabolic stability |
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| Institution: | 1. Department of Entomology and Nematology, and UC Davis 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, Russia;1. Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA;2. Department of Chemistry, Technology and Equipment of Chemical Industry, Volzhsky Polytechnic Institute (Branch) Volgograd State Technical University, Volzhsky, Russia;3. N.D. Zelinsky Institute of Organic Chemistry (ZIOC) of Russian Academy of Sciences, Moscow, Russia;1. Key Laboratory of Structure-Based Drugs Design and Discovery of Ministry of Education, Shenyang Pharmaceutical University, Shenyang, PR China;2. Department of Pharmacology, Shenyang Pharmaceutical University, Shenyang, PR China;3. Benxi Institute of Pharmaceutical Research, Shenyang Pharmaceutical University, Shenyang, PR China;1. Lomonosov Institute of Fine Chemical Technologies, Moscow Technological University, Moscow 117571, Russian Federation;2. Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany;3. Fraunhofer IME-TMP, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany;4. Institute of Physical and Theoretical Chemistry, Goethe University Frankfurt, Max-von-Laue-Straße 7, 60438 Frankfurt, Germany;5. School of Pharmacy, University of Eastern Finland, 70211 Kuopio, Finland;6. N. D. Zelinsky Institute of Organic Chemistry, 47 Leninsky Prospect, Moscow 119991, Russian Federation;7. Institute of Biochemistry, Goethe University Frankfurt, Max-von-Laue-Straße 9, 60438 Frankfurt, Germany;8. Saint Petersburg State University, Saint Petersburg 199034, Russian Federation;1. Department of Entomology and Nematology, UCD Comprehensive Cancer Center, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA;2. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California at San Diego, 9500 Gilman Drive, MC 0736, La Jolla, CA 92093, USA;3. Campus Mass Spectrometry Facilities, University of California at Davis, One Shields Avenue, Davis, CA 95616, USA;1. Department of Medicine, Columbia University, 650 W 168th Street, BB1029, New York, NY 10032, USA;2. University of California, Department of Internal Medicine, Division of Pulmonary, Critical Care, and Sleep Medicine, Davis, CA 95616, USA;3. Department of Entomology and UCD Cancer Center, University of California, Davis, CA 95616, USA;4. Department of Chemistry and Biochemistry, California State University, East Bay, 25800 Carlos Bee Boulevard, Hayward, CA 94542, USA |
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| Abstract: | Adamantyl groups are widely used in medicinal chemistry. However, metabolism limits their usage. Herein, we report the first systematic study of adamantyl ureas and diureas bearing substituents in bridgehead positions of adamantane and/or spacers between urea groups and adamantane group, and tested their effects on soluble epoxide hydrolase inhibitor potency and metabolic stability. Interestingly, the effect on activity against human and murine sEH varied in opposite ways with each new methyl group introduced into the molecule. Compounds with three methyl substituents in adamantane were very poor inhibitors of murine sEH while still very potent against human sEH. In addition, diureas with terminal groups bigger than sEH catalytic tunnel diameter were still good inhibitors suggesting that the active site of sEH opens to capture the substrate or inhibitor molecule. The introduction of one methyl group leads to 4-fold increase in potency without noticeable loss of metabolic stability compared to the unsubstituted adamantane. However, introduction of two or three methyl groups leads to 8-fold and 98-fold decrease in stability in human liver microsomes for the corresponding compounds. |
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| Keywords: | Soluble epoxide hydrolase Inhibitor Adamantane Isocyanate Urea |
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