C17,20-lyase inhibitors I.: Structure-based de novo design and SAR study of C17,20-lyase inhibitors
C17,20-lyase inhibitors I.: Structure-based de novo design and SAR study of C17,20-lyase inhibitors
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DOI：
10.1016/j.bmc.2004.02.007
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发表时间：
2004-05-01
影响因子：
3.5
通讯作者：
Tasaka, A
中科院分区：
文献类型：
--
作者：
Matsunaga, N;Kaku, T;Tasaka, A
基于其底物17 α-羟基双烯醇酮，采用从头设计法合成了新型非甾体C-17，C-20-裂解酶抑制剂，其中一些化合物表现出有效的C-17，C-20-裂解酶抑制作用。然而，在体内活动被发现是短暂的，为了提高作用的持续时间，一系列的苯并噻吩衍生物进行了评估。结果，具有纳摩尔酶抑制（IC 50 = 4-9 nM）的化合物9 h、（S）-9i和9 k以及9 e（IC 50 = 27 nM）被鉴定为具有强大的体内功效，具有延长的作用持续时间。体内有效性的关键结构决定因素被证明是苯并噻吩环上的5-氟基团和4-咪唑基部分。9 k和17 α-羟基双烯醇酮的叠加证明了它们的结构相似性，并使药理学结果合理化。此外，所选化合物也被鉴定为人酶的有效抑制剂，IC 50值为20-30 nM。(C)2004爱思唯尔有限公司保留所有权利。
Novel nonsteroidal C-17.20-lyase inhibitors were synthesized using de novo design based on its substrate, 17alpha-hydroxypregnenolone, and several compounds exhibited potent C-17,C-20-lyase inhibition. However, in vivo activities were found to be short-lasting, and in order to improve the duration of action, a series of benzothiophene derivatives were evaluated. As a result, compounds 9h, (S)-9i, and 9k with nanomolar enzyme inhibition (IC50 = 4-9 nM) and 9e (IC50 = 27 nM) were identified to have powerful in vivo efficacy with extended duration of action. The key structural determinants for the in vivo efficacy were demonstrated to be the 5-fluoro group on the benzothiophene ring and the 4-imidazolyl moiety. Superimposition of 9k and 17alpha-hydroxypregnenolone demonstrated their structural similarity and enabled rationalization of the pharmacological results. In addition, selected compounds were also identified to be potent inhibitors of human enzyme with IC50 values of 20-30 nM. (C) 2004 Elsevier Ltd. All rights reserved.