N -substituted 4-(4-carboxyphenoxy)benzamides. Synthesis and Evaluation as Inhibitors of Steroid-5α-reductase Type 1 and 2

Abstract

In search of non-steroidal inhibitors of human prostatic 5 α -reductase, we recently described N -substituted 4′-biphenyl-4-carboxylic acids. Here, we report the optimisation of this series of compounds by increasing the conformational flexibility using an ether linker between the steroidal A-C ring mimetics. Ten new compounds were synthesised and tested against human and rat isozymes 1 and 2. The substances showed a broad range of activity from 36% inhibition at a concentration of 10 μM to an IC 50 value of 60 nM for compounds 22 and 29 respectively. The most potent compound 26 showed an IC 50 value improved by a factor of 5 from 1.9 μM to 0.38 μM in comparison with the parent biphenyl compound 15.

Keywords::

• 5α-reductase
• Non-steroidal Inhibitors
• Isozymes 1 And 2
• N -substituted 4-(4-carboxyphenoxy)benzamides