体外和体内17β-N-(4-苯基氨基甲酰)雄激素-4-en-3- 1衍生物作为5a-还原酶抑制剂对雄激素依赖性腺体的影响

Q4 Pharmacology, Toxicology and Pharmaceutics
M. Cabeza, Lucero Bautista, E. Bratoeff, Juan Soriano, Y. Heuze
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引用次数: 0

摘要

5α-还原酶抑制剂已被证明可用于治疗前列腺疾病,这可能是由于5α-还原酶活性不受调节。本研究旨在测定4种不同的17β-苯基氨基甲酰雄安德-4-en-3-one1 -4衍生物作为5α-还原酶(5RD5A)抑制剂的活性,以改善现有药物的作用。化合物1-4对人前列腺酶5α-还原酶活性的体外影响,通过测定IC50值,测定抑制5rd5a2活性50%的化合物浓度。在体内,化合物1-4在前列腺肥大仓鼠模型中进行了药理作用鉴定。甾体17β-carboxamides 1,3,4 (IC50 = 5±0.5,0.112±0.045,0.167±0.056 nM)显著抑制5RD5A2酶的体外活性,其效价高于被称为5RD5A2特异性抑制剂的非那雄胺(IC50 = 8.5±0.3 nM)。化合物1、3、4比非那雄胺对睾酮处理的阉割仓鼠侧腹器官的减小作用更有效。此外,化合物1-4在减轻仓鼠模型前列腺重量方面比非那雄胺本身更有效,在六天的治疗期间没有产生毒理学效应。综上所述,甾体17 β-羧酰胺1-4是人类5rd5a2活性的合适抑制剂,除了能够降低前列腺重量而不产生毒性外。因此,这些类固醇在治疗良性前列腺增生方面具有良好的治疗潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
In vitro and In vivo Effects of 17β-N-(4-phenylcarbamoyl) androst-4-en-3- one Derivatives as 5a-reductase Inhibitors on Androgen-dependent Glands
5α-reductase inhibitors have been proven useful for the treatment of prostate diseases, which can be due to the unregulated activity of 5α-reductase enzyme. This study was focused on determining the activity of four different derivatives of 17β-phenyl carbamoyl-androst-4-en-3-one 1–4 as inhibitors of 5α-reductase (5RD5A), to improve the effects of current drugs. In vitro effect of compounds 1-4 on the activity of the human prostate enzyme, 5α-reductase, was determined by measuring IC50 values, the concentration of a compound that inhibits the activity of 5RD5A2 by 50%. In vivo, the pharmacological effects of compounds 1-4 were identified in a hamster model of prostate hypertrophy. The steroidal 17β-carboxamides 1, 3, and 4 (IC50 = 5±0.5, 0.112±0.045, 0.167±0.056 nM) significantly inhibited the in vitro activity of the 5RD5A2 enzyme with higher potency than finasteride, which is a drug known as a specific 5RD5A2 inhibitor (IC50 = 8.5±0.3 nM). Compounds 1, 3, and 4 were more potent than finasteride to decrease the size of hamster flank organs in castrated animals treated with testosterone. Also, compounds 1-4 were more effective than finasteride itself to reduce the weight of the prostate in the hamster model, without producing toxicological effects during the six days of treatment. In conclusion, the steroidal 17 β-carboxamides 1-4 were suitable inhibitors of human 5RD5A2 activity, in addition to being able to reduce prostate weight without causing toxicity. These steroids could, therefore, have promising therapeutic potential for the treatment of benign prostatic hyperplasia.
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来源期刊
Current Enzyme Inhibition
Current Enzyme Inhibition Pharmacology, Toxicology and Pharmaceutics-Drug Discovery
CiteScore
1.30
自引率
0.00%
发文量
30
期刊介绍: Current Enzyme Inhibition aims to publish all the latest and outstanding developments in enzyme inhibition studies with regards to the mechanisms of inhibitory processes of enzymes, recognition of active sites, and the discovery of agonists and antagonists, leading to the design and development of new drugs of significant therapeutic value. Each issue contains a series of timely, in-depth reviews written by leaders in the field, covering a range of enzymes that can be exploited for drug development. Current Enzyme Inhibition is an essential journal for every pharmaceutical and medicinal chemist who wishes to have up-to-date knowledge about each and every development in the study of enzyme inhibition.
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