Prostate cancer (PCa) is the most commonly diagnosed cancer in men and the second leading cause of death. Although PCa detected at an early stage can be successfully eradicated by radical prostatectomy and radiotherapy, there is unmet need for the treatment of castration-resistant PCa and metastatic disease. The aldo-keto reductase (AKRs) AKR1C3 isoform plays a vital role in the biosynthesis of androgens and is considered a validated target for treatment of PCa. However, no AKR1C3-targeted agent has yet been approved for clin. use. Nonsteroidal anti-inflammatory drugs (NSAIDs), asFlufenamic acid or Indomethacine, have been shown to inhibit AKR1C3-dependent processes in human cell lines and murine xenografts. However, the potential therapeutic usefulness of these NSAIDs in the context of castration-resistant prostate cancer (CRPC) is limited because of undesired side effects assocd. with chronic COX inhibition. Following the aim to identify the structural requirements necessary to obtain AKR1C3 inhibiting activity while simultaneously diminishing COX-2 affinity, in this occasion a successful bioisosteric replacement of the Flufenamic acid carboxylic acid with acidic hydroxylated triazoles is presented. Besides describing computationally supported design, synthesis and SAR, the novel series underwent biochem. investigation with focus on increasing selective inhibition of AKR1C3 over other key isoforms (AKR1C1 and 1C2), COX1 vs 2 selectivity and capacity to target AKR1C3 expression in VCaP and A549 cancer cell lines. [on SciFinder(R)]
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