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Nidufexor (LMB763), a Novel FXR Modulator for the Treatment of Nonalcoholic Steatohepatitis.
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-05 , DOI: 10.1021/acs.jmedchem.9b01621 Donatella Chianelli 1 , Paul V Rucker 1 , Jason Roland 1 , David C Tully 1, 2 , John Nelson 1 , Xiaodong Liu 1 , Badry Bursulaya 1 , Eloy D Hernandez 1 , Jane Wu 1 , Mahavir Prashad 3 , Thierry Schlama 4 , Yugang Liu 3 , Alan Chu 1 , James Schmeits 1 , David J Huang 1 , Robert Hill 1 , Dingjiu Bao 1 , Jocelyn Zoll 1 , Young Kim 1 , Todd Groessl 1 , Peter McNamara 1 , Bo Liu 1 , Wendy Richmond 1 , Ignacio Sancho-Martinez 1 , Andrew Phimister 2 , H Martin Seidel 1 , Michael K Badman 5 , Sean B Joseph 1 , Bryan Laffitte 1 , Valentina Molteni 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-02-05 , DOI: 10.1021/acs.jmedchem.9b01621 Donatella Chianelli 1 , Paul V Rucker 1 , Jason Roland 1 , David C Tully 1, 2 , John Nelson 1 , Xiaodong Liu 1 , Badry Bursulaya 1 , Eloy D Hernandez 1 , Jane Wu 1 , Mahavir Prashad 3 , Thierry Schlama 4 , Yugang Liu 3 , Alan Chu 1 , James Schmeits 1 , David J Huang 1 , Robert Hill 1 , Dingjiu Bao 1 , Jocelyn Zoll 1 , Young Kim 1 , Todd Groessl 1 , Peter McNamara 1 , Bo Liu 1 , Wendy Richmond 1 , Ignacio Sancho-Martinez 1 , Andrew Phimister 2 , H Martin Seidel 1 , Michael K Badman 5 , Sean B Joseph 1 , Bryan Laffitte 1 , Valentina Molteni 1
Affiliation
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Farnesoid X receptor (FXR) agonists are emerging as important potential therapeutics for the treatment of nonalcoholic steatohepatitis (NASH) patients, as they exert positive effects on multiple aspects of the disease. FXR agonists reduce lipid accumulation in the liver, hepatocellular inflammation, hepatic injury, and fibrosis. While there are currently no approved therapies for NASH, the bile acid-derived FXR agonist obeticholic acid (OCA; 6-ethyl chenodeoxycholic acid) has shown promise in clinical studies. Previously, we described the discovery of tropifexor (LJN452), the most potent non-bile acid FXR agonist currently in clinical investigation. Here, we report the discovery of a novel chemical series of non-bile acid FXR agonists based on a tricyclic dihydrochromenopyrazole core from which emerged nidufexor (LMB763), a compound with partial FXR agonistic activity in vitro and FXR-dependent gene modulation in vivo. Nidufexor has advanced to Phase 2 human clinical trials in patients with NASH and diabetic nephropathy.
中文翻译：
Nidufexor（LMB763），一种用于治疗非酒精性脂肪性肝炎的新型FXR调节剂。
法尼醇X受体（FXR）激动剂正在成为治疗非酒精性脂肪性肝炎（NASH）患者的重要潜在疗法，因为它们在疾病的多个方面发挥积极作用。FXR激动剂可减少肝脏中的脂质蓄积，肝细胞炎症，肝损伤和纤维化。尽管目前尚无批准用于NASH的疗法，但胆汁酸衍生的FXR激动剂奥贝胆酸（OCA； 6-乙基鹅去氧胆酸）已在临床研究中显示出希望。先前，我们描述了托拉非索（LJN452）的发现，托拉非索（LJN452）是目前临床研究中最有效的非胆汁酸FXR激动剂。在这里，我们报告了一种基于三环二氢铬基并吡唑核心的非胆汁酸FXR激动剂新化学系列的发现，该化合物从中出现了硝苯氟醚（LMB763），一种在体外具有部分FXR激动活性并在体内具有FXR依赖性基因调节的化合物。Nidufexor已针对NASH和糖尿病性肾病患者进行了2期人类临床试验。
更新日期：2020-01-15
中文翻译：
Nidufexor（LMB763），一种用于治疗非酒精性脂肪性肝炎的新型FXR调节剂。
法尼醇X受体（FXR）激动剂正在成为治疗非酒精性脂肪性肝炎（NASH）患者的重要潜在疗法，因为它们在疾病的多个方面发挥积极作用。FXR激动剂可减少肝脏中的脂质蓄积，肝细胞炎症，肝损伤和纤维化。尽管目前尚无批准用于NASH的疗法，但胆汁酸衍生的FXR激动剂奥贝胆酸（OCA； 6-乙基鹅去氧胆酸）已在临床研究中显示出希望。先前，我们描述了托拉非索（LJN452）的发现，托拉非索（LJN452）是目前临床研究中最有效的非胆汁酸FXR激动剂。在这里，我们报告了一种基于三环二氢铬基并吡唑核心的非胆汁酸FXR激动剂新化学系列的发现，该化合物从中出现了硝苯氟醚（LMB763），一种在体外具有部分FXR激动活性并在体内具有FXR依赖性基因调节的化合物。Nidufexor已针对NASH和糖尿病性肾病患者进行了2期人类临床试验。
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