Metabolism-Guided Selective Androgen Receptor Antagonists: Design, Synthesis, and Biological Evaluation for Activity against Enzalutamide-Resistant Prostate Cancer.
Metabolism-Guided Selective Androgen Receptor Antagonists: Design, Synthesis, and Biological Evaluation for Activity against Enzalutamide-Resistant Prostate Cancer.
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DOI：
10.1021/acs.jmedchem.2c01858
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发表时间：
2023-03-09
影响因子：
7.3
通讯作者：
Miller, Duane D.
中科院分区：
文献类型：
--
作者：
Hwang, Dong-Jin;He, Yali;Ponnusamy, Suriyan;Thiyagarajan, Thirumagal;Mohler, Michael L.;Narayanan, Ramesh;Miller, Duane D.
雄激素受体（AR）拮抗剂领域新药发现的一个主要挑战在于预测可药用性质，这将使小分子在体外和体内的进一步研究期间保持其效力和稳定性。吲哚（化合物8）是一类AR拮抗剂，具有非常高的效力（IC 50 = 0.085 μM），但代谢不稳定。在本文所述的代谢研究期间，我们合成了新的小分子，其表现出显著改善的稳定性，同时保留了对AR的有效拮抗活性。对分为三类（I类、II类和III类）的50多种化合物进行的结构-活性关系（SAR）研究发现了两种化合物（32 c和35 i），它们是有效的AR拮抗剂（例如，对于化合物35 i），IC 50 = 0.021 μM，T1/2 = 120 min。新拮抗剂在过表达AR（LNCaP-AR）的Hershberger和抗雄激素Enz-Res肿瘤异种移植模型中表现出改善的体内药代动力学（PK）和高效抗雄激素活性。
A major challenge for new drug discovery in the area of androgen receptor (AR) antagonists lies in predicting the druggable properties that will enable small molecules to retain their potency and stability during further studies in vitro and in vivo. Indole (compound 8) is a first-in-class AR antagonist with very high potency (IC50 = 0.085 μM) but is metabolically unstable. During the metabolic studies described herein, we synthesized new small molecules that exhibit significantly improved stability while retaining potent antagonistic activity for an AR. This structure–activity relationship (SAR) study of more than 50 compounds classified with three classes (Class I, II, and III) and discovered two compounds (32c and 35i) that are potent AR antagonists (e.g., IC50 = 0.021 μM, T1/2 = 120 min for compound 35i). The new antagonists exhibited improved in vivo pharmacokinetics (PK) with high efficacy antiandrogen activity in Hershberger and antiandrogen Enz-Res tumor xenograft models that overexpress AR (LNCaP-AR).
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影响因子：
4.5
作者：
Gibbons JA;Ouatas T;Krauwinkel W;Ohtsu Y;van der Walt JS;Beddo V;de Vries M;Mordenti J
通讯作者：
Mordenti J
影响因子：
5.2
作者：
Banjare, Shyam Kumar;Nanda, Tanmayee;Ravikumar, P. C.
通讯作者：
Ravikumar, P. C.
影响因子：
4.8
作者：
Jones, Amanda;Chen, Jiyun;Dalton, James T.
通讯作者：
Dalton, James T.
影响因子：
1.8
作者：
MIYAURA, N;YAMADA, K;SUZUKI, A
通讯作者：
SUZUKI, A
DOI：
10.1006/bbrc.1998.8209
发表时间：
1998-03-06
影响因子：
3.1
作者：
Dalton, JT;Mukherjee, A;Miller, DD
通讯作者：
Miller, DD