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Design, synthesis and biological evaluation of novel androst-3,5-diene-3-carboxylic acid derivatives as inhibitors of 5α-reductase type 1 and 2.

Abstract
5α-Reductase is a key enzyme responsible for dihydrotestosterone biosynthesis and has been recognized as an important target for discovering new drugs against benign prostatic hyperplasia (BPH). In this study, a series of novel steroidal androst-3,5-diene-3-carboxylic acids have been designed and synthesized. Biological evaluations were performed on their 5α-reductase inhibitory activities by both in vitro enzyme inhibition assay and in vivo by prostate weighing method. Results showed that most of them displayed excellent 5α-reductase inhibitory potency. Detailed evaluation indicated that most of the compounds displayed slightly higher inhibition potency towards type 2 isozyme. Among all the compounds, 16a was found to be the most potential inhibitor with the IC50 of 0.25μM and 0.13μM against type 1 and 2 isozymes respectively. In vivo 5a-reductase inhibitory evaluation of 16a also showed a more significant reduction effect (p<0.001) in rat prostate weight than epristeride. Furthermore, the results of in silico ADME study indicated that compound 16a exhibited good pharmacokinetic properties. Thus, 16a could serve as promising lead candidates for further study.
AuthorsKejing Lao, Jie Sun, Chong Wang, Weiting Lyu, Boshen Zhou, Ruheng Zhao, Qian Xu, Qidong You, Hua Xiang
JournalSteroids (Steroids) Vol. 124 Pg. 29-34 (08 2017) ISSN: 1878-5867 [Electronic] United States
PMID28549802 (Publication Type: Journal Article)
CopyrightCopyright © 2017. Published by Elsevier Inc.
Chemical References
  • 5-alpha Reductase Inhibitors
  • Carboxylic Acids
  • Cholestenone 5 alpha-Reductase
Topics
  • 5-alpha Reductase Inhibitors (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
  • Animals
  • Carboxylic Acids (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
  • Chemistry Techniques, Synthetic
  • Cholestenone 5 alpha-Reductase (metabolism)
  • Computer Simulation
  • Drug Design
  • Male
  • Rats

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