An aerosolised dual-action Autotaxin inhibitor-PPARγ agonist for the treatment of pulmonary fibrosis.

Fibrosis is a significant mortality factor and health concern, promoting organ malfunction as well as immune and chemical resistance. Among the different fibroproliferative diseases, idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic interstitial lung disease (ILD) with limited therapeutic options. Autotaxin, a novel therapeutic target in IPF, is a secreted lysophospholipase D catalysing the extracellular production of lysophosphatidic acid (LPA), a growth-factor-like signalling phospholipid. The pathologic effects of LPA in the lung include the suppression of peroxisome proliferator-activated receptor γ (PPARγ), a therapeutic target in metabolic disorders, frequent comorbidities of IPF associated with unfavourable prognosis. In this report, we introduce EL244, the first-in-class dual ATX inhibitor and PPARγ agonist endowed with drug-like properties. Developed through chemoinformatic repositioning, innovative rational design, synthesis and pharmacological evaluation, EL244 exhibited favourable ADMET and PK/PD profiles. Remarkably, EL244 inhalation, which alleviates systemic toxicity concerns, decreased pulmonary LPA levels and related effects in pulmonary cells, and attenuated bleomycin (BLM)-induced pulmonary fibrosis, restoring respiratory functions. Therefore, EL244 emerges as a promising investigational new drug candidate for the inhaled treatment of IPF and ILDs.