Preclinical and clinical data suggest that acetyl-CoA carboxylase (ACC) inhibitors have the potential to rebalance disordered lipid metabolism, leading to improvements in nonalcoholic steatohepatitis (NASH). Consistent with these observations, first-in-human clinical trials with our ACC inhibitor PF-05175157 led to robust reduction of de novo lipogenesis (DNL), albeit with concomitant reductions in platelet count, which were attributed to the inhibition of fatty acid synthesis within bone marrow. Herein, we describe the design, synthesis, and evaluation of carboxylic acid-based ACC inhibitors with organic anion transporting polypeptide (OATP) substrate properties, which facilitated selective distribution of the compounds at the therapeutic site of action (liver) relative to the periphery. These efforts led to the discovery of clinical candidate PF-05221304 (12), which selectively inhibits liver DNL in animals, while demonstrating considerable safety margins against platelet reduction in a nonhuman primate model.

中文翻译：

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通过肝脏靶向优化乙酰辅酶A羧化酶抑制剂的收益/风险。

临床前和临床数据表明，乙酰辅酶A羧化酶（ACC）抑制剂具有重新平衡紊乱的脂质代谢的潜力，从而改善了非酒精性脂肪性肝炎（NASH）。与这些观察结果一致，使用我们的ACC抑制剂PF-05175157进行的首次人类临床试验导致从头脂肪形成（DNL）的有效减少，尽管伴随血小板数量的减少，这归因于脂肪酸在体内的合成受到抑制骨髓。在本文中，我们描述了具有有机阴离子转运多肽（OATP）底物特性的基于羧酸的ACC抑制剂的设计，合成和评估，该抑制剂可促进化合物相对于外围在治疗作用部位（肝脏）的选择性分布。12），其选择性抑制动物肝脏DNL，同时在非人灵长类动物模型中显示出相当大的安全性，可防止血小板减少。