Development of Tricyclic 4,5-Dihydro-3<i>H</i>-pyrrolo[2,3-<i>c</i>]quinolin-4-ones as Potent Autotaxin Inhibitors for Pulmonary Fibrosis Treatment <i>In Vivo</i>

Autotaxin (ATX) has been recognized as an attractive target due to its hyperactivity in hydrolyzing lysophosphatidylcholine (LPC) into lysophosphatidic acid (LPA) throughout the initiation and progression of fibrotic diseases. Herein, a hydrophilic amide linker and sp³-rich bicyclic 4,5,6,7-tetrahydro-7<i>H</i>-pyrazolo[3,4-<i>c</i>]pyridin-7-one scaffold were employed to modify the lead compound PAT-409, followed by benzene ring fusion to generate novel tricyclic 4,5-dihydro-3<i>H</i>-pyrrolo[2,3-<i>c</i>]quinolin-4-one ATX inhibitors. Among them, the pyridine-2-carboxylic derivatives <b>45</b> and <b>46</b> demonstrated subnanomolar ATX inhibition (IC₅₀ < 1 nM), with a favorable heart safety profile (hERG > 30 μM) and minimal fibroblast toxicity. Significantly, in bleomycin-induced pulmonary fibrosis mouse models, both compounds markedly improved respiratory function and reduced fibrotic lesions. Mechanistic studies revealed that <b>45</b> suppressed the TGF-β/Smad signaling pathway, downregulating α-smooth muscle actin (α-SMA) and extracellular matrix components (ECM). Overall, the identification of <b>45</b> and <b>46</b> for pulmonary fibrosis therapy provides a featured tricyclic scaffold for further development of novel ATX inhibitors.