| 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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MedLine Citation:
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PMID: 22391033 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 28h 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. |
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Authors:
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Satoshi Yamamoto; Naoki Tomita; Yuri Suzuki; Tomohiko Suzaki; Tomohiro Kaku; Takahito Hara; Masuo Yamaoka; Naoyuki Kanzaki; Atsushi Hasuoka; Atsuo Baba; Mitsuhiro Ito |
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Publication Detail:
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Type: JOURNAL ARTICLE Date: 2012-2-10 |
Journal Detail:
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Title: Bioorganic & medicinal chemistry Volume: - ISSN: 1464-3391 ISO Abbreviation: - Publication Date: 2012 Feb |
Date Detail:
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Created Date: 2012-3-6 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 9413298 Medline TA: Bioorg Med Chem Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Copyright Information:
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Copyright © 2012 Elsevier Ltd. All rights reserved. |
Affiliation:
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Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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