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ID: ALA3112445

Journal: Bioorg Med Chem Lett

Title: Design and synthesis of prostate cancer antigen-1 (PCA-1/ALKBH3) inhibitors as anti-prostate cancer drugs.

Authors: Nakao S, Mabuchi M, Shimizu T, Itoh Y, Takeuchi Y, Ueda M, Mizuno H, Shigi N, Ohshio I, Jinguji K, Ueda Y, Yamamoto M, Furukawa T, Aoki S, Tsujikawa K, Tanaka A.

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.

CiteXplore: 24461353

DOI: 10.1016/j.bmcl.2014.01.008