Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase.
Structure-activity relationships of amide-phosphonate derivatives as inhibitors of the human soluble epoxide hydrolase (sEH) were investigated. First, a series of alkyl or aryl groups were substituted on the carbon alpha to the phosphonate function in amide compounds to see whether substituted phosphonates can act as a secondary pharmacophore. A tert-butyl group (16) on the alpha carbon was found to yield most potent inhibition on the target enzyme. A 4-50-fold drop in inhibition was induced by other substituents such as aryls, substituted aryls, cycloalkyls, and alkyls. Then, the modification of the O-substituents on the phosphonate function revealed that diethyl groups (16 and 23) were preferable for inhibition to other longer alkyls or substituted alkyls. In amide compounds with the optimized diethylphosphonate moiety and an alkyl substitution such as adamantane (16), tetrahydronaphthalene (31), or adamantanemethane (36), highly potent inhibitions were gained. In addition, the resulting potent amide-phosphonate compounds had reasonable water solubility, suggesting that substituted phosphonates in amide inhibitors are effective for both inhibition potency on the human sEH and water solubility as a secondary pharmacophore.
Department of Applied Bioscience, Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan.
In-Hae
IH
Kim
Department of Medicinal Chemistry, Hyundai Pharm Co., Ltd, Suwon, Gyonggi 443-270, Republic of Korea.
Yong-Kyu
YK
Park
Department of Applied Bioscience, Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan.
Hisashi
H
Nishiwaki
Department of Entomology and Nematology, and UCD Comprehensive Cancer Center, University of California, One Shields Ave, Davis, CA 95616, USA.
Bruce D
BD
Hammock
Department of Applied Bioscience, Faculty of Agriculture, Ehime University, 3-5-7 Tarumi, Matsuyama, Ehime 790-8566, Japan. Electronic address: knishi@agr.ehime-u.ac.jp.
Kosuke
K
Nishi
D000218:Adamantane / Q000031:analogs & derivatives; D000577:Amides / Q000737:chemistry*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004851:Epoxide Hydrolases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D063065:Organophosphonates / Q000737:chemistry* / Q000494:pharmacology*; D011485:Protein Binding; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics; D012995:Solubility; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000737:chemistry; D014508:Urea / Q000737:chemistry
D000577:Amides; D004791:Enzyme Inhibitors; D063065:Organophosphonates; D011994:Recombinant Proteins; D013764:Tetrahydronaphthalenes; D014508:Urea; D004851:Epoxide Hydrolases; D000218:Adamantane
Amide–phosphonate derivatives; Inhibitors; Soluble epoxide hydrolase