Discovery of the S1P2 Antagonist GLPG2938 (1-[2-Ethoxy-6-(trifluoromethyl)-4-pyridyl]-3-[[5-methyl-6-[1-methyl-3-(trifluoromethyl)pyrazol-4-yl]pyridazin-3-yl]methyl]urea), a Preclinical Candidate for the Treatment of Idiopathic Pulmonary Fibrosis

Mounting evidence from the literature
suggests that blocking S1P2
receptor (S1PR2) signaling could be effective for the treatment of
idiopathic pulmonary fibrosis (IPF). However, only a few antagonists
have been so far disclosed. A chemical enablement strategy led to
the discovery of a pyridine series with good antagonist activity.
A pyridazine series with improved lipophilic efficiency and with no
CYP inhibition liability was identified by scaffold hopping. Further
optimization led to the discovery of 40 (GLPG2938), a
compound with exquisite potency on a phenotypic IL8 release assay,
good pharmacokinetics, and good activity in a bleomycin-induced model
of pulmonary fibrosis.

现有大量文献证据表明，阻断S1P2受体（S1PR2）信号通路可用于特发性肺纤维化（IPF）的治疗。但截至目前，仅有少数此类拮抗剂被公开报道。研究人员通过化学赋能策略，发现了一类具备良好拮抗活性的吡啶类化合物系列。经骨架跃迁技术，又鉴定出一类亲脂性效率更优且无细胞色素P450（CYP）抑制隐患的哒嗪类化合物系列。经过进一步优化，最终得到化合物40（GLPG2938）：该化合物在表型IL-8释放实验中展现出极佳的效价，同时具备良好的药代动力学特性，且在博莱霉素诱导的肺纤维化模型中表现出优异的治疗活性。