2,3-Diarylpropenoic acids as selective non-steroidal inhibitors of type-5 17β-hydroxysteroid dehydrogenase (AKR1C3)

The aldo–keto reductase AKR1C3 is an important target for the development of new drugs. Selective inhibitors of this enzyme are needed because they should not inhibit other, structurally closely related AKR1C isoforms. A comprehensive series of 2,3-diarylpropenoic acids was synthesized and evaluated for the inhibition of AKR1C1–AKR1C3. We found that the 4-methylsulfonylphenyl substituent at position 2 of these acids is required to exhibit the selective inhibition of AKR1C3. The best results were obtained for the compounds that fulfill the above requirement and possess a 4-bromophenyl, 4-methylthiophenyl, 4-methylphenyl or 4-ethylphenyl substituent at position 3 of the substituted propenoic acids (i.e., acids 28, 29, 37, and 39, respectively). These compounds represent an important step toward the development of drug candidates for a treatment of the hormone-dependent and hormone-independent forms of prostate and breast cancers.

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► A series of new 2,3-diarylpropenoic acids were prepared.
► The compounds were evaluated for their inhibition of aldo-keto reductases.
► Selective inhibitors of AKR1C3 were identified.
► Substituents on benzene rings play a crucial role in selective inhibition of AKR1C3.