Synthesis, Biological Evaluation and in silico Studies of Novel 5α-aza-Bhomo-3,5-secosteroids as Potential 5-reductase Inhibitors

Author(s): Rajnish Kumar, Pankaj Chauhan, Priyanka Malla, Manoj K. Mahapatra, Rolf W. Hartmann, Jörg Haupenthal, Manoj Kumar

Journal Name: Letters in Drug Design & Discovery

Volume 13 , Issue 9 , 2016

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Graphical Abstract:


Benign prostatic hyperplasia is non-malignant enlargement of prostate gland which results in severe lower urinary tract symptoms and affects the quality of life of patients. 5-Reductase inhibitors play a crucial role in the management of benign prostatic diseases with low toxicity and have been a major thrust area for its application in prostate cancers with limited success. In continuation of our program to develop novel 5-reductase inhibitors, we report herein the synthesis and biological evaluation of 5a-oxo-5-aza-B-homo-3,5-seco-4-nor-cholestan-3-oic acid and 25(R)-5a-oxo-5-aza- B-homo-3,5-seco-4-nor-spirostan-3-oic acid derivatives. In vitro evaluation using human embryonic kidney cell line (HEK) based assay revealed compound MK-234 as most potent inhibitor with an IC50 value of 0.474 ±0.041 M followed by MK-233 with an IC50 value 4.84 ± 0.088 µM as compared to clinically used drug finasteride (IC50 = 30.3 nM). Compound MK-235 and MK-236 also exhibited moderate inhibition with an IC50 value of 9.24 ± 0.796 and 13.148 ± 0.379 µM, respectively. Additionally, in silico ADME predictive studies were also carried out to assess the ‘druggability properties’ of the synthesised compounds.

Keywords: Benign prostatic hyperplasia, 5α-reductase inhibitors, 3, 5-seco steroids, in silico predictive ADME studies.

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Article Details

Year: 2016
Page: [869 - 878]
Pages: 10
DOI: 10.2174/1570180813666160630110649
Price: $65

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