Environmental Health Science Laboratory, Sumitomo Chemical Co., Ltd, 1-98, Kasugadenaka 3-chome, Konohana-ku, Osaka 554-8558, Japan.
Bioorg Med Chem. 2012 May 15;20(10):3242-54. doi: 10.1016/j.bmc.2012.03.052. Epub 2012 Apr 1.
We have previously reported the discovery of a new class of potent inhibitors of 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) derived from benzylidene oxazolidinedione and thiazolidinedione scaffolds. In this study, these analogs were designed, synthesized, and evaluated in a human cell-based assay. The detailed structure-activity relationship (SAR) surrounding this pharmacophore were developed, and consequently a number of compounds from this series demonstrated single-digit nanomolar 17β-HDS3 inhibitory activity in vitro. Subsequent optimization work in pursuit of the improvement of oral bioavailability demonstrated in vivo proof-of-concept by prodrug strategy based on phosphate esters for these 17β-HSD3 inhibitors. When a phosphate ester 16 was administered orally at a high dose of 100mg/kg, 16 showed approximately two times more potent testosterone (T)-lowering effect against a positive control in the luteinizing hormone-releasing hormone (LH-RH)-induced T production assay. The T-lowering effect continued at ca 10% level of control over 4h after administration. The nonsteroidal molecules based on this series have the potential to provide unique and effective clinical opportunities for treatment of prostate cancer.
我们之前报道过从苯亚甲基恶唑烷酮和噻唑烷二酮支架中发现了一类新型的强效 17β-羟甾脱氢酶 3（17β-HSD3）抑制剂。在这项研究中，我们设计、合成了这些类似物，并在基于人细胞的测定中进行了评估。围绕这个药效团，我们深入研究了详细的构效关系（SAR），因此该系列中的一些化合物在体外显示出了具有纳摩尔级别的对 17β-HSD3 的抑制活性。随后，我们通过磷酸酯前药策略对这些 17β-HSD3 抑制剂进行了优化，以提高其口服生物利用度，从而在体内证明了这一策略的概念验证。当磷酸酯 16 以 100mg/kg 的高剂量口服给药时，与阳性对照物相比，在黄体生成素释放激素（LH-RH）诱导的 T 产生测定中，16 对睾酮（T）的降低作用大约增强了两倍。给药后 4 小时内，T 的降低作用持续在对照的 10%左右。基于该系列的非甾体分子有潜力为治疗前列腺癌提供独特且有效的临床机会。
