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 5alpha-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 microM to an IC50 value of 60 nM for compounds 22 and 29 respectively. The most potent compound 26 showed an IC50 value improved by a factor of 5 from 1.9 microM to 0.38 microM in comparison with the parent biphenyl compound 15.

A Connection between the Mitochondrial Permeability Transition Pore, Autophagy, and Cerebral Amyloidogenesis

“…Interestingly, we have a gender-specific in vivo situation in the APPPS model. In the rodent brain, sexual differentiation probably involves the activation of both 5α-reductase 2 and aromatase enzymes in a sex- and time-specific pattern, , but 5-α-reductase type 1, which is predominant, is not differentially expressed between sexes . The enzyme converts a number of steroids with a C3 ketone group and a C4−C5 double bond (delta4; androgens, progestins and glucocorticoids) to their 5α-reduced metabolites and has been shown to be localized in both neuronal and glial cells.…”

Novel 5α-Reductase Inhibitors: Synthesis, Structure−Activity Studies, and Pharmacokinetic Profile of Phenoxybenzoylphenyl Acetic Acids

“…Consequently, we and other groups have focused on the synthesis and evaluation of nonsteroidal inhibitors. [16][17][18][19][20][21][22][23][24][25][26][27][28][29] Recently, we have discovered a novel type of dual inhibition of 5R-reductase 1 and 2, a concept which is called hybrid inhibition. 30 Esters of substituted benzylidene-4-carboxylic acids are inhibitors of type 1 enzyme.…”

“…It is well-tolerated and side effects, e.g., sexual disorders and gynecomastia, are transient. , Fewer side effects might be exhibited by appropriate nonsteroidal inhibitors. Consequently, we and other groups have focused on the synthesis and evaluation of nonsteroidal inhibitors. − Recently, we have discovered a novel type of dual inhibition of 5α-reductase 1 and 2, a concept which is called hybrid inhibition . Esters of substituted benzylidene-4-carboxylic acids are inhibitors of type 1 enzyme .…”

Cyclohex‐1‐ene Carboxylic Acids: Synthesis and Biological Evaluation of Novel Inhibitors of Human 5α Reductase

“…Finasteride and Epristeride (Chart 1) are highly potent steroidal inhibitors, the former having been used for the treatment of BPH for some years [7,8]. Because of the side effects of steroidal drugs which in part are due to their steroidal structure, we and other groups have been trying to develop nonsteroidal compounds [9]. In different classes we found highly active compounds in vitro.…”