Abstract Rationale Tager et al. (2008) identified LPA1 as a therapeutic target for the potential treatment of idiopathic pulmonary fibrosis (IPF). AM152 (BMS-986020), the first LPA1 antagonist tested clinically, demonstrated potential for clinical efficacy in Phase 2; however, development was terminated due to hepatobiliary toxicity. BMS-986278, a second-generation antagonist dosed twice daily, resolved hepatobiliary toxicity but hypotension surfaced as a potential safety issue. We present PIPE-791, a novel LPA1 antagonist, offering superior target occupancy with once-daily dosing and reduced LPA-induced hemodynamic effects, potentially enhancing patient safety. Methods For LPA1 occupancy, mice received vehicle, PIPE-791, or BMS-986278 followed by intravenous 3H-PIPE-497, an LPA1-selective radioligand. Lungs were removed, homogenized, and filtered to determine membrane bound radioactivity. To determine vascular cell effects, primary human aortic smooth muscle cells (hASMC) were cultured, loaded with calcium dye, and compound added at varying times prior to LPA challenge. The inhibitory activity of each antagonist on LPA-induced calcium mobilization was measured by fluorescence. Vascular effects were also measured in vivo using laser speckle contrast imaging. Mice received PIPE-791 or BMS-986278 and challenged 1hr later with intravenous LPA. Continuous cutaneous blood flow was monitored. Results Both antagonists achieved high LPA1 lung occupancy 3hrs post dose but only PIPE-791 provided sustained coverage from 3hrs to 24hrs. The corresponding ED50s for PIPE-791 were 0.5 and 0.1 (mg/kg), respectively. In contrast, BMS-986278 occupancy rapidly declined from 3hrs to 24hrs, with ED50s of 7.5 and 100 (mg/kg), respectively. Differentiation was also evident in vascular assays. Both compounds inhibited LPA-induced hASMC calcium mobilization, but the effect of PIPE-791 was delayed as reflected by an IC50 10 µM with 5-min preincubation shifting to 21 nM with longer (3hr) preincubation (450-fold difference). A nominal shift was noted for BMS-986278 (396 nM to 149 nM, ∼3-fold). Differentiation recapitulated in vivo. LPA challenge caused a rapid and sustained decrease in cutaneous blood flow. At pharmacologically equivalent dose levels, BMS-986278, but not PIPE-791, inhibited this response. Conclusions PIPE-791 demonstrates superior lung receptor occupancy with sustained coverage after a single dose. This effect is attributed to the long receptor residence time shown for PIPE-791 in binding studies. PIPE-791 also showed delayed LPA-induced vascular responses. This likely results from slow receptor association which differs from antagonists with rapid on-rate kinetics such as BMS-986278. Although speculative, this unique pharmacology may mitigate hemodynamic responses observed clinically with prior LPA1 antagonists thereby offering a safer, once daily, therapeutic for patients with IPF. This abstract is funded by: Contineum Therapeutics
Lorrain et al. (Fri,) studied this question.