Design, synthesis, and biological evaluation of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole derivatives as novel androgen receptor antagonists.
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Yamamoto S, Tomita N, Suzuki Y, Suzaki T, Kaku T, Hara T, Yamaoka M, Kanzaki N, Hasuoka A, Baba A, Ito M
Design, synthesis, and biological evaluation of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole derivatives as novel androgen receptor antagonists.
Bioorg Med Chem. 2012 Apr 1;20(7):2338-52. doi: 10.1016/j.bmc.2012.02.005. Epub 2012 Feb 10.
- PubMed ID
- 22391033 [ View in PubMed]
- Abstract
A series of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole compounds B were designed, synthesized, and evaluated for their potential as new-generation androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a bulky amide substituent (R(2)) to the terminal aryl ring of the 4-arylmethyl group favored the reduction of agonistic activity and improved the pharmacokinetic (PK) properties. Similarly, introduction of a bulky substituent in the 4-aryloxy derivatives also resulted in improved PK properties. Compounds 28 h and 44b exhibited potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft model. On the contrary, bicalutamide showed only partial suppression of tumor growth. These results suggest that the novel pyrazole derivatives are new-generation AR antagonists, different from the 'first-generation' antagonists such as bicalutamide in a CRPC treatment model.
DrugBank Data that Cites this Article
- Binding Properties
Drug Target Property Measurement pH Temperature (°C) Bicalutamide Androgen receptor EC 50 (nM) >10000 N/A N/A Details Bicalutamide Androgen receptor IC 50 (nM) 330 N/A N/A Details Bicalutamide Androgen receptor IC 50 (nM) 54 N/A N/A Details