Synthesis and biological evaluation of 3-tetrazolo steroidal analogs: Novel class of 5α-reductase inhibitors

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• 作者：Saurabh Aggarwal^a ; Manoj Kumar Mahapatra^a ; Rajnish Kumar^a ; Tilak R. Bhardwaj^a ; ^b ; Rolf W. Hartmann^c ; ^d ; Jö ; rg Haupenthal^c ; Manoj Kumar^a ; ^{manoj_uips@pu.ac.in" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Tetrazole ; 5AR ; HEK ; Finasteride ; Testosterone
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：24
• 期：4
• 页码：779-788
• 全文大小：1056 K

文摘

In the present study, a series of steroidal tetrazole derivatives of androstane and pregnane have been prepared in which the tetrazole moiety was appended at C-3 and 17a-aza locations. 3-Tetrazolo-3,5-androstadien-17-one (ass="boldFont">6), 3-tetrazolo-19-nor-3,5-androstadien-17-one (ass="boldFont">10), 3-tetrazolo-3,5-pregnadien-20-one (ass="boldFont">14), 17a-substituted 3-tetrazolo-17a-aza-an class="smallcaps">dan>-homo-3,5-androstadien-17-one (ass="boldFont">26&ndash;ass="boldFont">31) and 3-(2-acetyltetrazolo)-17a-aza-an class="smallcaps">dan>-homo-3,5-androstadien-17-one (ass="boldFont">32) were synthesized from dehydroepiandrosterone acetate (1) through multiple synthetic steps. Some of the synthesized compounds were evaluated for their in vitro 5α-reductase (5AR) inhibitory activity by measuring the conversion of [³H] androstenedione in human embryonic kidney (HEK) cells. In vivo 5α-reductase inhibitory activity also showed a significant reduction (p <0.05) in rat prostate weight. The most potent compound ass="boldFont">14 showed 5AR-2 inhibition with IC₅₀ being 15.6 nM as compared to clinically used drug finasteride (40 nM). There was also a significant inhibition of 5AR-1 with IC₅₀ 547 nM compared to finasteride (453 nM).