Discovery of\nNovel 4,5,6,7-Tetrahydro‑7<i>H</i>‑pyrazolo[3,4‑<i>c</i>]pyridin-7-one\nDerivatives as Orally Efficacious ATX Allosteric Inhibitors for the\nTreatment of Pulmonary Fibrosis

Pulmonary fibrosis (PF) is a progressive, fatal lung\ndisease lacking\neffective treatments. Autotaxin (ATX) plays a crucial role in exacerbating\ninflammation and fibrosis, making it a promising target for fibrosis\ntherapies. Herein, starting from PAT-409 (Cudetaxestat), a series\nof novel ATX inhibitors bearing 1<i>H</i>-indole-3-carboxamide,\n4,5,6,7-tetrahydro-7<i>H</i>-pyrazolo[3,4-<i>c</i>]pyridin-7-one, or 4,5,6,7-tetrahydro-1<i>H</i>-pyrazolo[4,3-<i>c</i>]pyridine cores were designed based on the structure of\nATX hydrophobic tunnel. The optimal <b>31</b> and <b>35</b> inhibited ATX with IC<sub>50</sub> values of 2.8 and 0.7 nM, respectively.\nIn a bleomycin-induced mouse PF model, both compounds significantly\nreduced fibrosis by regulating the TGF-β/Smad signaling pathway\nand downregulating collagen deposition. Furthermore, <b>35</b> exhibited both negligibly low hERG channel inhibition (IC<sub>50</sub> > 30 μM) and remarkable microsomal stability. Notably, <b>35</b> was characterized by favorable pharmacokinetic properties\n(<i>F</i> = 69.5%) and excellent safety <i>in vivo</i>. Overall, <b>35</b> turned out to be a well-characterized\npotent and safe ATX inhibitor warranting further investigation for\nthe treatment of PF.