Autotaxin (ATX), a major source of the lipid mediator lysophosphatidic acid (LPA), plays a critical role in the pathogenesis and progression of pulmonary fibrosis. In this study, with the aim of developing novel ATX inhibitors with preferred lipophilicity, structure-based optimizations of PAT-409 were carried out, leading to the identification of two novel orally active ATX inhibitors, 4 and 29, with IC