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Bioisosteric substitution of adamantane with bicyclic lipophilic groups improves water solubility of human soluble epoxide hydrolase inhibitors
- Burmistrov, Vladimir;
- Morisseau, Christophe;
- Karlov, Dmitry;
- Pitushkin, Dmitry;
- Vernigora, Andrey;
- Rasskazova, Elena;
- Butov, Gennady M;
- Hammock, Bruce D
Published Web Location
https://doi.org/10.1016/j.bmcl.2020.127430Abstract
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.
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