| Literature DB >> 24461353 |
Syuhei Nakao1, Miyuki Mabuchi2, Tadashi Shimizu1, Yoshihiro Itoh1, Yuko Takeuchi1, Masahiro Ueda1, Hiroaki Mizuno2, Naoko Shigi3, Ikumi Ohshio3, Kentaro Jinguji3, Yuko Ueda3, Masatatsu Yamamoto4, Tatsuhiko Furukawa4, Shunji Aoki5, Kazutake Tsujikawa3, Akito Tanaka6.
Abstract
A series of 1-aryl-3,4-substituted-1H-pyrazol-5-ol derivatives was synthesized and evaluated as prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors to obtain a novel anti-prostate cancer drug. After modifying 1-(1H-benzimidazol-2-yl)-3,4-dimethyl-1H-pyrazol-5-ol (1), a hit compound found during random screening using a recombinant PCA-1/ALKBH3, 1-(1H-5-methylbenzimidazol-2-yl)-4-benzyl-3-methyl-1H-pyrazol-5-ol (35, HUHS015), was obtained as a potent PCA-1/ALKBH3 inhibitor both in vitro and in vivo. The bioavailability (BA) of 35 was 7.2% in rats after oral administration. As expected, continuously administering 35 significantly suppressed the growth of DU145 cells, which are human hormone-independent prostate cancer cells, in a mouse xenograft model without untoward effects.Entities:
Keywords: ALKBH3; Anti-prostate cancer drug; Bioavailability; Inhibitor; PCA-1; Small compound
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Year: 2014 PMID： 24461353 DOI： 10.1016/j.bmcl.2014.01.008
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823