143782-23-4Relevant articles and documents
Spirocyclic Thiohydantoin Antagonists of F877L and Wild-Type Androgen Receptor for Castration-Resistant Prostate Cancer
Zhang, Zhuming,Connolly, Peter J.,Trabalón Escolar, Luis,Rocaboy, Christian,Pande, Vineet,Meerpoel, Lieven,Lim, Heng-Keang,Branch, Jonathan R.,Ondrus, Janine,Hickson, Ian,Bush, Tammy L.,Bischoff, James R.,Bignan, Gilles
, p. 1245 - 1252 (2021)
Androgen receptor (AR) transcriptional reactivation plays a key role in the development and progression of lethal castration-resistant prostate cancer (CRPC). Recurrent alterations in the AR enable persistent AR pathway signaling and drive resistance to the treatment of second-generation antiandrogens. AR F877L, a point mutation in the ligand binding domain of the AR, was identified in patients who acquired resistance to enzalutamide or apalutamide. In parallel to our previous structure-activity relationship (SAR) studies of compound 4 (JNJ-pan-AR) and clinical stage compound 5 (JNJ-63576253), we discovered additional AR antagonists that provide opportunities for future development. Here we report a highly potent series of spirocyclic thiohydantoins as AR antagonists for the treatment of the F877L mutant and wild-type CRPC.
Exploring the tetrahydroisoquinoline thiohydantoin scaffold blockade the androgen receptor as potent anti-prostate cancer agents
Xu, Xi,Ge, Raoling,Li, Lei,Wang, Jubo,Lu, Xiaoyu,Xue, Siqi,Chen, Xijing,Li, Zhiyu,Bian, Jinlei
, p. 1325 - 1344 (2018)
Prostate cancer (PC) is a major cause of cancer-related male death in worldwide and the identification of new and improved potent anti-PC molecules is constantly required. A novel scaffold of tetrahydroisoquinoline thiohydantoin was rationally designed based on the enzalutamide structures and our pre-work, leading to the discovery of a series of new antiproliferative compounds. Several new analogues displayed improved androgen receptor (AR) antagonistic activity, while maintaining the higher selective toxicity toward LNCaP cells (AR-rich) versus DU145 cells (AR-deficient) compared to enzalutamide. In fact, compound 55 exhibited promising in vitro antitumor activity by impairing AR unclear translocation. More importantly, 55 showed better pharmacokinetic properties compared to the compound 1 reported in our pre-work. These results demonstrate a step towards the development of novel and improved AR antagonists.
Synthesis method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile
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Paragraph 0012; 0026; 0029-0030-0031; 0034-0035, (2021/06/02)
The invention discloses a synthesis method of 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. The synthesis method comprises the following steps: with 3-trifluoromethyl-4-cyanobenzoic acid as an initial raw material, firstly, subjecting 3-trifluoromethyl-4-cyanobenzoic acid to reacting with diphenyl azidophosphate under an anhydrous condition to generate 4-isocyanato-2-(trifluoromethyl)benzonitrile, and then subjecting 4-isocyanato-2-(trifluoromethyl)benzonitrile to reacting with a Lawson reagent to obtain the compound 4-isothiocyanato-2-(trifluoromethyl)benzonitrile. The method has the advantages of simple synthetic route, one-pot reaction, mild reaction conditions, simple post-treatment, high product yield (wherein total yield is greater than or equal to 83.9%), and easy industrial production.
Design, synthesis and biological evaluation of novel thiohydantoin derivatives as potent androgen receptor antagonists for the treatment of prostate cancer
Wang, Ao,Wang, Yawan,Meng, Xin,Yang, Yushe
, (2021/01/07)
Prostate cancer (PC) is the most common malignancy in men worldwide. Here, two series of novel thiohydantoin derivatives of enzalutamide as potent androgen receptor (AR) antagonists were designed and synthesized. Among them, compound 31c was identified as an AR antagonist which is 2.3–fold more potent than enzalutamide. Molecular docking studies were performed to explain the improved potency of 31c at AR. In cell proliferation assays, 31c exhibited similar anti-proliferative activities with enzalutamide against hormone sensitive LNCaP cells and AR-overexpressing LNCaP/AR cells. These data indicate that 31c can be a good lead compound for further structure optimization for the treatment of prostate cancer.