Bioisosteric substitution of adamantane with bicyclic lipophilic groups improves water solubility of human soluble epoxide hydrolase inhibitors

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:30

Article

Burmistrov, Vladimir^1,2,6  Morisseau, Christophe¹  Karlov, Dmitry^3,4,5  Pitushkin, Dmitry^2,6  Vernigora, Andrey⁶  Rasskazova, Elena⁶  Butov, Gennady M.²  Hammock, Bruce D.¹ 

[1] Univ Calif Davis, Comprehens Canc Ctr, Dept Entomol & Nematol, Davis, CA 95616 USA

[2] Volgograd State Tech Univ, Dept Chem Technol & Equipment Chem Ind, Volzhsky Polytech Inst Branch, Volzhsky 404121, Russia

[3] Skolkovo Innovat Ctr, Skolkovo Inst Sci & Technol, Moscow 143026, Russia

[4] Lomonosov Moscow State Univ, Dept Chem, Moscow 119991, Russia

[5] Russian Acad Sci, Inst Physiologically Act Cpds, Chernogolovka 142432, Moscow Region, Russia

[6] Volgograd State Tech Univ, Sch Chem, Volgograd 400131, Russia

关键词: Soluble epoxide hydrolase;    Inhibitor;    Adamantane;    Urea;    Camphor;    Norcamphane;   

DOI  :  10.1016/j.bmcl.2020.127430

来源: Elsevier

【 摘 要 】

A series of inhibitors of the soluble epoxide hydrolase (sEH) containing lipophilic groups of natural origin (camphanyl, norcamphanyl, furan-2-yl) were developed. Inhibitory potency ranging from 0.4 nM to 2.16 mu M were obtained. While having the same level of inhibitory activity bicyclic ureas are up to 10-fold more soluble than the corresponding ureas containing adamantyl or 4-trifluoromethoxyphenyl substituents. This makes them easier to formulate, more bioavailable and thus more promising as therapeutic sEH inhibitors. Endo/exo-form of compound 2b derived from L-camphor is 14-fold more potent than the corresponding analogue derived from D-camphor (IC50 = 3.7 nM vs. 50.6 nM) indicating enantiomeric preference.

【 授权许可】

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