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.