Inhibitors Of Human 5α-reductase Research Articles

Synthesis and biological evaluation of novel unsaturated carboxysteroids as human 5α-reductase inhibitors: A legitimate approach

In the present study, novel steroidal 17a-substituted 3-cyano-17a-aza-D-homo-3,5-androstadien-17-ones (12–19) and 17a-substituted 17-oxo-17a-aza-D-homo-3,5-androstadien-3-oic acids (20–26) were synthesized from dehydroepiandrosterone acetate (6) along with 17-oxo-19-nor-3,5-androstadien-3-oic acid (30) through a multistep synthesis. Compounds were evaluated for their in vitro 5α-reductase inhibitory activity by measuring the conversion of [3H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity was also determined using rat prostate weighing method. Compounds 21–23 and 25 showed potent inhibition of 5α-reductase II enzyme with IC50 values of 54.1 ± 9.5, 22.1 ± 2.4, 72.8 ± 2.3 and 26.5 ± 4.4 nM respectively as compared to Finasteride (30.3 nM) along with a significant (p < 0.05) reduction in rat prostate weight.

Self-organizing molecular field analysis on pregnane derivatives as human steroidal 5α-reductase inhibitors

Normal growth and development of human prostate is regulated by the androgens which balances cell proliferation and apoptosis. Testosterone (T) and dihydrotestosterone (DHT) are the two key androgens that stimulate most of the androgen action in prostate. Testosterone is converted to DHT by the membrane bound NADPH-dependent 5α-reductase enzyme. As a consequence of the important observation that progesterone and deoxycortisone inhibits the synthesis of DHT by competing with 4-en-3-one function of the testosterone for the 5α-reductase enzyme a number of pregnane derivatives were synthesized and have been reported as inhibitors of human 5α-reductase enzyme. Due to lack of information on the crystal structure of human 5α-reductase, ligand-based 3D-QSAR study has been performed on pregnane derivatives using self-organizing molecular field analysis (SOMFA) for rationalizing the molecular properties and human 5α-reductase inhibitory activities. The statistical results having good cross-validated rcv2 (0.881), non-cross-validated r2 (0.893) and F-test value (175.527), showed satisfied predictive ability rpred2 (0.777). Analysis of SOMFA models through electrostatic and shape grids provide useful information for the design and optimization of steroidal structure as novel human 5α-reductase inhibitors.

3,3-Diphenylpentane skeleton as a steroid skeleton substitute: Novel inhibitors of human 5α-reductase 1

We designed and synthesized novel type 1 5α-reductase inhibitors by using 3,3-diphenylpentane skeleton as a substitute for the usual steroid skeleton. 4-(3-(4-( N-Methylacetamido)phenyl)pentan-3-yl)phenyl dibenzylcarbamate ( 11k) is a competitive 5α-reductase inhibitor with the IC 50 value of 0.84 μM.

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

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Cyclohex-1-ene carboxylic acids: synthesis and biological evaluation of novel inhibitors of human 5 alpha reductase.

In search of novel nonsteroidal mimics of steroidal inhibitors of 5 alpha reductase, 4-(2-phenylethyl)cyclohex-1-ene carboxylic acids 1-5 were synthesized with different substituents in para position of the phenyl ring (1: N, N-diisopropylcarbamoyl, 2: phenyl, 3: phenoxy, 4: benzoyl, and 5: benzyl). The principal synthetic approach for the desired compounds consisted of a Wittig olefination between 1, 4-dioxaspiro [4.5]-decane-8-carbaldehyde (4g and the appropriate phosphonium salts. The compounds were tested for inhibition of human 5 alpha reductase isozymes 1 and 2 using DU 145 cells and preparations from prostatic tissue, respectively. They turned out to be good inhibitors of the prostatic isozyme 2 with compound 1 being the most potent one (IC(50) = 760 nM). Isozyme 1 was only slightly inhibited. It is concluded that the novel structures are appropriate for being further optimized, aiming at the development of a novel drug for the treatment of benign prostatic hyperplasia.

6-Substituted 3,4-Dihydro-naphthalene-2-carboxylic Acids: Synthesis and Structure-Activity Studies in a Novel Class of Human 5α Reductase Inhibitors

Novel 3,4-dihydro-naphthalene-2-carboxylic acids were synthesized and evaluated for 5 α reductase inhibitory activity. This enzyme exists in two isoforms and is a pharmacological target for the treatment of benign prostatic hyperplasia, male pattern baldness and acne. In the present study non-steroidal compounds capable of mimicking the transition state of the steroidal substrates were prepared. The synthetic strategy for the preparation of compounds 1 - 6 consisted of triflation followed by subsequent Heck-type carboxylation or methoxy carbonylation for 6-phenyl-3,4-dihydro-naphthalen-2(1H)-one 1c. A Negishi-type coupling reaction between 6-(trifluoro-methanesulfonyloxy)-3,4-dihydro-naphthalene-2-carboxylic acid methyl ester 7b and various aryl bromides led, after further transformations, to 6-substituted 3,4-dihydro-naphthalene-2-carboxylic acids 7 - 15. In a similar way the corresponding naphthalene-2-carboxylic acids 16 and 17 were obtained. The DU 145 cell line and prostate homogenates served as enzyme sources for the human type 1 and type 2 isozymes, whereas ventral prostate was employed to evaluate rat isozyme inhibitory potency. The most active inhibitors identified in this study were 6-[4- (N, N -dicyclohexylaminocarbonyl)phenyl]-3,4-dihydro-naphthalene-2-carboxylic acid (3) (IC 50 =0.09 μM, rat type 1), 6-[3- (N, N -dicyclohexylaminocarbonyl)phenyl]-3,4-dihydro-naphthalene-2-carboxylic acid (13) (IC 50 =0.75 μM, human type 2; IC 50 =0.81 μM, human type 1) and 6-[4- (N, N -diisopropylamino-carbonyl)phenyl]naphthalene-2-carboxylic acid (16) (IC 50 =0.2 μM, human type 2). The latter compound was shown to deactivate the enzyme in an uncompetitive manner (Ki=90 nM; Km, Testosterone=0.8-1.0 μM) similar to the steroidal inhibitor Epristeride. Select inhibitors (13 and 16) were tested in vivo using testosterone propionate-treated, juvenile, orchiectomized SD-rats. None of the compounds was active at a dose of 25 mg/kg. This result might in part be ascribed to the relatively poor in vitro rat isozyme inhibitory potency.

Synthesis of 4,17-diazasteroid inhibitors of human 5α-reductase

The synthesis of the 17-aza isomer of finasteride is described. With the side chain amide group of the compound existing in the Z configuration the structure is similar to one of the two favored conformations of finasteride. A series of 4.17-diazasteroids was assayed against the isoenzymes of human 5α-reductase.