Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India.
Departments of Small Molecule Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States.
J Med Chem. 2022 Jul 14;65(13):8948-8960. doi: 10.1021/acs.jmedchem.2c00165. Epub 2022 Jun 15.
While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of in the liver and ileum by FXR agonists in vivo. Compound demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.
虽然几种正在临床研究中用于治疗非酒精性脂肪性肝炎（NASH）的法尼醇 X 受体（FXR）激动剂显示出了有益的效果，但瘙痒和血浆脂质升高等不良反应限制了它们的临床疗效和可批准性。在此，我们报告了化合物 （BMS-986339）的发现和临床前评估，这是一种非胆汁酸 FXR 激动剂，与我们之前报道的激动剂 BMS-986318 相比，具有药理学上不同的特征。化合物 在体外和体内均表现出对 FXR 的有效激活，尽管其特征存在一定的依赖性，导致体内产生组织选择性效应。据我们所知，这是第一个报告表明 FXR 激动剂在体内对肝脏和回肠中 的不同诱导作用。尽管肝脏中某些基因的激活程度降低，但化合物 仍表现出强大的抗纤维化功效，这表明 BMS-986318 的其他药理学作用并不能进一步提高疗效，这可能为减少不良反应提供了机会。需要进一步在人类中进行评估以验证这一假设。
