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,Journal of Medicinal Chemistry

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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
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-05-03 , DOI: 10.1021/acs.jmedchem.1c00138
Oscar Mammoliti ₁ , Adeline Palisse ₁ , Caroline Joannesse ₁ , Sandy El Bkassiny ₁ , Brigitte Allart ₁ , Alex Jaunet ₁ , Christel Menet ₁ , Beatrice Coornaert ₁ , Kathleen Sonck ₁ , Inge Duys ₁ , Philippe Clément-Lacroix ₂ , Line Oste ₁ , Monica Borgonovi ₂ , Emanuelle Wakselman ₂ , Thierry Christophe ₁ , Nicolas Houvenaghel ₁ , Mia Jans ₁ , Bertrand Heckmann ₂ , Laurent Sanière ₂ , Reginald Brys ₁

Affiliation

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.

中文翻译：

发现S1P2拮抗剂GLPG2938（1- [2-乙氧基-6-（三氟甲基）-4-吡啶基] -3-[[5-甲基-6- [1-甲基-3-（三氟甲基）吡唑-4-基] pyridazin-3-yl] methyl] urea），一种治疗特发性肺纤维化的临床前候选药物

越来越多的文献表明，阻断S1P2受体（S1PR2）信号传导可能有效治疗特发性肺纤维化（IPF）。然而，到目前为止，仅公开了几种拮抗剂。化学促成策略导致发现具有良好拮抗剂活性的吡啶系列。通过支架跳跃鉴定了具有改善的亲脂性效率并且没有CYP抑制责任的哒嗪系列。进一步的优化导致了40（GLPG2938）的发现，该化合物对表型IL8释放测定具有出色的功效，在博莱霉素诱导的肺纤维化模型中具有良好的药代动力学和良好的活性。

更新日期：2021-05-13

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