Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and fatal lung disease with limited approved treatment options. The lysophosphatidic acid receptor 1 (LPA1) antagonist BMS-986020 was efficacious in slowing lung function decline in a 6-month placebo-controlled Phase 2 clinical trial in patients with IPF, as measured by rate of decline of forced vital capacity (FVC). Futher clinical development of BMS-986020 was discontinued due to the occurrence of cases of hepatobiliary toxicity, which was attributed to the inhibition of key bile acid and phospholipid transporters (e.g. BSEP, IC50 4.7 µM; MDR3 IC50 3.2 µM) by BMS-986020. In order to address this issue (and to improve on the physicochemical profile of BMS-986020), a medicinal chemistry strategy of concomitantly increasing the C(sp3)/C(sp2) ratio as well as the overall polarity of BMS-986020 was implemented. The medicinal chemistry effort which resulted in the discovery of BMS-986278, a novel, potent LPA1 receptor antagonist currently in clinical development, will be discussed. BMS-986278 exhibits: 1) potent in vitro activity (including in lung fibroblasts); 2) inhibition of acute LPA-stimulated histamine release in mice in vivo; and 3) antifibrotic activity, as demonstrated by histopathological analysis (e.g. decreases in picrosirius red staining area) of lung tissue in chronic studies in the rodent bleomycin lung fibrosis model. BMS-986278 has a favorable preclinical ADME profile: 1) good pharmacokinetics, including high oral bioavailability, in rodents and monkeys, and 2) minimal hepatic metabolism (N-demethylation and acyl glucuronidation); it also has an improved physicochemical profile versus BMS-986020 (increased crystalline aqueous solubility and decreased plasma protein binding). In contrast to BMS-986020, BMS-986278 has negligible activity at bile acid and other clinically relevant drug transporters such as BSEP and MDR3 (IC50 &gt;100 µM). BMS-986278 is thus a novel, promising LPA1 receptor antagonist for the treatment of IPF and other fibrotic diseases.

Discovery of LPA receptor antagonist clinical candidate BMS-986278 for the treatment of idiopathic pulmonary fibrosis:  Preclinical pharmacological in vitro and in vivo evaluation

ACS Fall 2020 Virtual Meeting

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