Rational design and synthesis of 6-(piperazin-1-yl)imidazo[1,2-b]pyridazine derivatives as dual FXR/PPARδ agonists for treatment of pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive multifactorial lung disorder characterized by excessive deposition of fibrotic connective tissue. The activation of farnesoid X receptor (FXR) and Peroxisome Proliferator-activated Receptor δ (PPARδ) demonstrated therapeutic efficacy in reducing fibrotic pathology, respectively, suggesting that dual FXR/PPARδ up-regulators may provide a prospective approach to address the polypharmacy dilemma in fibrotic diseases. Herein, the identification campaign of 6-(piperazin-1-yl)imidazo[1,2-b]pyridazine derivatives as FXR/PPARδ dual agonists was described through hybridation of FXR Agonist GW-4064 and PPARδ Agonist GW-0742. The following exhaustive in vitro FXR and PPARδ activation studies culminated in the optimization of compound 10g, which displayed potent dual-target activities with an FXR agonistic EC₅₀ of 12.28 nM and 69 % PPARδ activation at 100 nM. In a Bleomycin-induced murine in vivo pulmonary fibrosis model, 10g (40 mg/kg, QD) significantly attenuated Collagen deposition and reduced the expression of α-SMA in lung tissue. Taken together, these results shed new light on the discovery of novel FXR/PPARδ agonists for the treatment of IPF.

Antifibrosis; FXR /PPAR dual agonist; IPF; SAR; imidazo[1,2-b]pyridazine.