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

ABSTRACT: 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 μM 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.

SUBMITTER: Burmistrov V

PROVIDER: S-EPMC7494652 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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

Burmistrov Vladimir V Morisseau Christophe C Karlov Dmitry D Pitushkin Dmitry D Vernigora Andrey A Rasskazova Elena E Butov Gennady M GM Hammock Bruce D BD

Bioorganic & medicinal chemistry letters 20200724 18

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 μM 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 t ...[more]

PMID: 32736212

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