Design, Synthesis,\nand Activity of a Novel Series\nof Pyridazine-Based ALK5 Inhibitors

ALK5 inhibitors represent an attractive therapeutic approach\nfor\nthe treatment of a variety of pathologies, including cancer and fibrosis.\nHerein, we report the design and <i>in vitro</i> characterization\nof a novel series of ALK5 modulators featuring a 4,6-disubstituted\npyridazine core. A knowledge-based scaffold-hopping exploration was\ninitially conducted on a restricted set of heteroaromatic cores using\navailable ligand- and structure-based information. The most potent\nstructurally novel hit compound <b>2A</b> was subsequently subjected\nto a preliminary optimization for the inhaled delivery, applying physicochemical\ncriteria aimed at minimizing systemic exposure to limit the risk of\nadverse side effects. The resulting inhibitors showed a marked boost\nin potency against ALK5 and <i>in vitro</i> ADME properties,\npotentially favoring lung retention. The optimized hits <b>20</b> and <b>23</b> might thus be considered promising starting\npoints for the development of novel inhaled ALK5 inhibitors.