BMS-986278 is an orally active, high-affinity and potent small molecule LPA1 antagonist that is commonly used in the study of progressive fibrotic interstitial lung disease[1][2].
Cytotoxicity for BMS-986278( 0-100μM;24h,72h ) was not observed in human hepatocytes (IC50 >100 μM)[1]. BMS-986278 is a high-affinity LPA1 antagonist, with Kbs of 6.9 nM and 4.0 nM for human and mouse LPA1 in CHO cells overexpressing LPA1[3].
BMS-986278 (30,100 and 300 mg/kg; 6 months) found centrilobular hepatocyte hypertrophy in the liver and gallbladder at 300 mg/kg/day and a dose-dependent increase in alkaline phosphatase (ALP) at all doses (≤ 2.3-fold), total bilirubin (TBILI) was dose-dependently increased (≤ 3.0-fold) only at the 100 mg/kg/day dose [2].BMS-986278(20, 50 and 100 mg/kg/day；1 month) produced a dose-dependent increase in plasma total bile acid (BA) levels in female monkeys [2].
References：
[1]. Gill MW, Murphy BJ, Cheng PTW, Sivaraman L, Davis M, Lehman-McKeeman L. Mechanism of hepatobiliary toxicity of the LPA1 antagonist BMS-986020 developed to treat idiopathic pulmonary fibrosis: Contrasts with BMS-986234 and BMS-986278. Toxicol Appl Pharmacol. 2022 Mar 1;438:115885.
[2]. Sivaraman L, Gill M, Nelson DM, Chadwick KD. Structure dependence and species sensitivity of in vivo hepatobiliary toxicity with lysophosphatidic acid receptor 1 (LPA1) antagonists. Toxicol Appl Pharmacol. 2022 Mar 1;438:115846.
[3].Cheng PTW, Kaltenbach RF 3rd, Zhang H, et al.Discovery of an Oxycyclohexyl Acid Lysophosphatidic Acid Receptor 1 (LPA1) Antagonist BMS-986278 for the Treatment of Pulmonary Fibrotic Diseases. J Med Chem. 2021 Nov 11;64(21):15549-15581.
BMS-986278是一种具有口服活性、高亲和力、强效的小分子 LPA1 拮抗剂，常用于进行性纤维化间质性肺病的研究[1][2]。
在人肝细胞中未观察到 BMS-986278（0-100μM；24h、72h）的细胞毒性（IC50 >100 μM）[1]。 BMS-986278 是一种高亲和力 LPA1 拮抗剂，在过表达 LPA1 的 CHO 细胞中，对人和小鼠 LPA1 的 Kbs 分别为 6.9 nM 和 4.0 nM[3]。
BMS-986278（30、100 和 300 mg/kg；6 个月）在 300 mg/kg/day剂量下发现肝脏和胆囊中的中心小叶肝细胞肥大，并且所有剂量下碱性磷酸酶 (ALP) 呈剂量依赖性增加（≤ 2.3 倍），总胆红素 (TBILI) 仅在 100 mg/kg/day 剂量下呈剂量依赖性增加（≤ 3.0 倍）[2]。BMS-986278（20、50 和 100 mg/kg/day；6个月）在雌性猴子中产生剂量依赖性血浆总胆汁酸 (BA) 水平增加[2]。