Lao Kejing, Sun Jie, Wang Chong, Lyu Weiting, Zhou Boshen, Zhao Ruheng, Xu Qian, You Qidong, Xiang Hua
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
Steroids. 2017 Aug;124:29-34. doi: 10.1016/j.steroids.2017.05.011. Epub 2017 May 24.
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 IC 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.
5α-还原酶是负责双氢睾酮生物合成的关键酶，并且已被公认为是发现抗良性前列腺增生（BPH）新药的重要靶点。在本研究中，设计并合成了一系列新型甾体雄甾-3,5-二烯-3-羧酸。通过体外酶抑制试验和体内前列腺称重法对它们的5α-还原酶抑制活性进行了生物学评价。结果表明，它们中的大多数表现出优异的5α-还原酶抑制效力。详细评价表明，大多数化合物对2型同工酶的抑制效力略高。在所有化合物中，发现16a是最具潜力的抑制剂，对1型和2型同工酶的IC50分别为0.25μM和0.13μM。16a的体内5α-还原酶抑制评价还显示，与依立雄胺相比，大鼠前列腺重量的减轻效果更显著（p<0.001）。此外，计算机辅助的ADME研究结果表明，化合物16a具有良好的药代动力学性质。因此，16a可作为有前景的先导候选物用于进一步研究。
