LPA1 receptor antagonist 1

LPA1 receptor antagonist 1 is a highly selective Lysophosphatidic Acid receptor-1 (LPA1) antagonist with an IC₅₀ of 25 nM. IC50 & Target: IC50: 25 nM (LPA1)^[1]. In Vitro: LPA1 receptor antagonist 1 (compound 2) displays very potent and highly selective inhibitory activity toward LPA1, with little inhibition on LPA3 even at very high concentrations. To our knowledge, LPA1 receptor antagonist 1 is the most selective nonlipid LPA1 antagonist so far reported. It appears that compounds (e.g., LPA1 receptor antagonist 1) from the N-aryltriazole chemical class are much more selective for LPA1 than compounds from the corresponding pyrazole series. In comparison with Ki16425 and AM095, LPA1 receptor antagonist 1 shows much improved antiproliferative activity. LPA1 receptor antagonist 1 demonstrates the highest LPA1 selectivity and attenuated LPA-induced NHLF proliferation and contraction with high potency^[1]. In Vivo: Oral dosing of LPA1 receptor antagonist 1 in mice causes a dose-dependent reduction in serum histamine levels induced following intravenous LPA stimulation. When mice are orally dosed with LPA1 antagonist 1 (100 mg/kg, aqueous suspension) prior to intravenous LPA injection, the LPA-induced histamine level is significantly blocked A clear PK/PD relationship is demonstrated by the correlation between the levels of LPA1 receptor antagonist 1 and LPA-induced histamine concentrations in plasma. Although AM095 almost completely blocks histamine release (100 mg/kg), analysis of plasma samples revealed more than 65-fold higher concentrations of AM095 than LPA1 receptor antagonist 1 (100 mg/kg). The ability of LPA1 receptor antagonist 1 to block histamine release at much lower plasma concentration suggests that further improvement of pharmacokinetic properties of this chemical class could lower the effective dose^[1].