Inhibition of mitochondrial pyruvate transport via the mitochondrial pyruvate carrier (MPC) has shown beneficial effects in treating metabolic diseases, certain cancers, various forms of neurodegeneration, and hair loss. These benefits arise either from the direct inhibition of mitochondrial pyruvate metabolism or from the metabolic rewiring when pyruvate entry is inhibited. However, current MPC inhibitors are either nonspecific or possess poor pharmacokinetic properties. To address this, approximately 50 pyrazole-based MPC inhibitors were synthesized to explore the structure-activity relationship for MPC inhibition, evaluated through inhibition of mitochondrial pyruvate respiration. These inhibitors were designed with increased steric hindrance around electron-deficient double bonds, allowing for refined structural modifications that reduce their potential to act as Michael acceptors. Additionally, the new MPC inhibitors directly inhibited stellate cell activation, indicating their potential as therapeutic candidates for metabolic dysfunction-associated steatohepatitis (MASH). Unlike the thiazolidinedione class of MPC inhibitors, these compounds did not activate the nuclear receptor PPARγ. Molecular modeling was conducted to explore interactions between these novel inhibitors and the MPC complex. We have identified the chemical determinants critical for MPC inhibition and successfully developed novel inhibitors that are potent, specific and possess excellent physicochemical properties, high solubility, and outstanding metabolic stability in human liver microsomes.

中文翻译：

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推进线粒体治疗学：靶向线粒体丙酮酸载体的吡唑基抑制剂的合成和药理学评价


通过线粒体丙酮酸载体 （MPC） 抑制线粒体丙酮酸转运在治疗代谢疾病、某些癌症、各种形式的神经退行性和脱发方面显示出有益作用。这些好处来自于直接抑制线粒体丙酮酸代谢或来自丙酮酸进入受到抑制时的代谢重新布线。然而，目前的 MPC 抑制剂要么是非特异性的，要么药代动力学特性差。为了解决这个问题，合成了大约 50 种基于吡唑的 MPC 抑制剂，以探索 MPC 抑制的结构-活性关系，通过抑制线粒体丙酮酸呼吸来评估。这些抑制剂在设计上增加了缺电子双键周围的空间位阻，允许进行精细的结构修饰，从而降低它们作为 Michael 受体的潜力。此外，新的 MPC 抑制剂直接抑制星状细胞活化，表明它们有可能成为代谢功能障碍相关脂肪性肝炎 （MASH） 的治疗候选者。与噻唑烷二酮类 MPC 抑制剂不同，这些化合物不会激活核受体 PPARγ。进行分子建模以探索这些新型抑制剂与 MPC 复合物之间的相互作用。我们已经确定了对 MPC 抑制至关重要的化学决定因素，并成功开发了有效的、特异性的、在人肝微粒体中具有优异理化性质、高溶解度和出色代谢稳定性的新型抑制剂。