RESUMO
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.
Assuntos
Desenho de Fármacos , Fibrose Pulmonar Idiopática/tratamento farmacológico , Piridazinas/química , Piridazinas/farmacologia , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores , Animais , Células CHO , Cricetulus , Humanos , Fibrose Pulmonar Idiopática/metabolismo , Interleucina-8/metabolismo , Masculino , Camundongos , Piridazinas/farmacocinética , Piridazinas/uso terapêutico , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease. Current treatments only slow down disease progression, making new therapeutic strategies compelling. Increasing evidence suggests that S1P2 antagonists could be effective agents against fibrotic diseases. Our compound collection was mined for molecules possessing substructure features associated with S1P2 activity. The weakly potent indole hit 6 evolved into a potent phthalazone series, bearing a carboxylic acid, with the aid of a homology model. Suboptimal pharmacokinetics of a benzimidazole subseries were improved by modifications targeting potential interactions with transporters, based on concepts deriving from the extended clearance classification system (ECCS). Scaffold hopping, as a part of a chemical enablement strategy, permitted the rapid exploration of the position adjacent to the carboxylic acid. Compound 38, with good pharmacokinetics and in vitro potency, was efficacious at 10 mg/kg BID in three different in vivo mouse models of fibrotic diseases in a therapeutic setting.