220001-53-6Relevant articles and documents
QSAR analysis of the inhibition of recombinant CYP 3A4 activity by structurally diverse compounds using a genetic algorithm-combined partial least squares method
Wanchana, Suchada,Yamashita, Fumiyoshi,Hashida, Mitsuru
, p. 1401 - 1408 (2003)
Purpose. To develop a quantitative structure/activity relationship (QSAR) model for predicting drug-CYP 3A4 interactions. Method. The inhibitory effect of 53 structurally diverse drugs on the metabolism of 7-benzyloxy-4-trifluoromethyl coumarin (BFC) by recombinant CYP 3A4 was evaluated using a rapid microtiter plate assay. For each drug, a total of 220 two-dimensional topological indices were calculated using Molconn-Z software. Using a genetic algorithm-based partial least squares (GA-PLS) method, the desired descriptors were automatically selected to maximize the predictability of the IC50 values. Results. The IC50 values of the drugs tested ranged from 9 nM to 2 mM. Based on the GA-PLS method, five principal components derived from 20 Molconn-Z descriptors were found to be effective for QSAR modeling. Interestingly, these descriptors suggested that the molecular size would be an important factor in determining drug-CYP 3A4 interactions). In the leave-one-out prediction, the rpred and the standard error of prediction (s) were 0.754 and 0.787, respectively. Even in an external validation, the predictions were in good agreement with experimental values (rpred = 0.744, s = 0.769, n = 9). Conclusions. The proposed model, in which two-dimensional topological descriptors were used as molecular descriptors, was able to predict drug-CYP 3A4 interactions with reasonable accuracy.
Discovery of a Novel Androgen Receptor Antagonist Manifesting Evidence to Disrupt the Dimerization of the Ligand-Binding Domain via Attenuating the Hydrogen-Bonding Network between the Two Monomers
Chai, Xin,Duan, Mojie,Fu, Weitao,Gong, Zhou,Hou, Tingjun,Lei, Yixuan,Li, Dan,Liao, Jianing,Pang, Jinping,Shan, Luhu,Sheng, Rong,Tang, Chun,Tang, Qing,Wang, Xuwen,Xu, Xiaohong,Zhang, Minkui
, p. 17221 - 17238 (2021/12/06)
Androgen receptor (AR) has proved to be a vital drug target for treating prostate cancer. Here, we reported the discovery of a novel AR antagonist 92 targeting the AR ligand-binding pocket, but distinct from the marketed drug enzalutamide (Enz), 92 demonstrated inhibition on the AR ligand-binding domain (LBD) dimerization, which is a novel mechanism reported for the first time. First, a novel hit (26, IC50 = 5.57 μM) was identified through virtual screening based on a theoretical AR LBD dimer bound with the Enz model. Then, guided by molecular modeling, 92 was discovered with 32.7-fold improved AR antagonistic activity (IC50 = 0.17 μM). Besides showing high bioactivity and safety, 92 can inhibit AR nuclear translocation. Furthermore, 92 inhibited the formation of the AR LBD dimer, possibly through attenuating the hydrogen-bonding network between the two monomers. This interesting finding would pave the way for the discovery of a new class of AR antagonists.
Benzopyrone or quinolinone compound and application thereof
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, (2020/08/25)
The invention discloses a benzopyrone or quinolinone compound and application thereof in preparation of a medicine for treating prostatic cancer, and belongs to the field of medicines. The benzopyroneand quinolinone compound with the structural formula as shown in the formula (I) has obvious antagonistic activity on androgen receptors and also has inhibitory activity on prostate cancer cells which do not express the androgen receptors. Therefore, the compound can be used as an androgen receptor antagonist to be applied to treatment of diseases related to androgen receptors or treatment of various metastatic prostate cancers, and a new choice is provided for development of drugs for treating prostate cancers.
Synthesis of 7-alkoxy-4-trifluoromethylcoumarins via the von Pechmann reaction catalyzed by molecular iodine
Degrote, Jami,Tyndall, Stephen,Wong, Koon Fai,Vanalstine-Parris, Melissa
supporting information, p. 6715 - 6717 (2015/01/09)
The synthesis of a series of 7-alkoxy-4-trifluoromethylcoumarins via the von Pechmann reaction catalyzed by molecular iodine is described. The reaction protocol is simple, inexpensive and leads to the formation of the corresponding coumarin derivatives in good yield and high purity. A key intermediate as well as several iodo byproducts were isolated.
Coumarin-based CYP3A fluorescent assay reagents
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, (2008/06/13)
Novel fluorescent substrates of human cytochrome P450 enzymes are provided. Also provided are methods for their manufacture and use. These substrates are useful in assessing cytochrome P450 enzyme activity and in selecting compounds which inhibit cytochrome P450 enzyme activity and, in particular, for identifying potential adverse drug interactions which are mediated by inhibition of cytochrome P450 enzyme activity. The compounds are particularly useful for assessing cytochrome P450 CYP3A enzyme activity.
