Discovery of <i>N</i>‑(3-Carbamoyl-5,5,7,7-tetramethyl-5,7-dihydro‑4<i>H</i>‑thieno[2,3‑<i>c</i>]pyran-2-yl)‑l<i>H</i>‑pyrazole-5-carboxamide (GLPG1837), a Novel Potentiator Which Can Open Class III Mutant Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) Channels to a High Extent

Cystic fibrosis (CF) is caused by mutations in the gene for the cystic fibrosis transmembrane conductance regulator (CFTR). With the discovery of Ivacaftor and Orkambi, it has been shown that CFTR function can be partially restored by administering one or more small molecules. These molecules aim at either enhancing the amount of CFTR on the cell surface (correctors) or at improving the gating function of the CFTR channel (potentiators). Here we describe the discovery of a novel potentiator GLPG1837, which shows enhanced efficacy on CFTR mutants harboring class III mutations compared to Ivacaftor, the first marketed potentiator. The optimization of potency, efficacy, and pharmacokinetic profile will be described

Discovery, Structure–Activity Relationship, and Binding Mode of an Imidazo[1,2‑<i>a</i>]pyridine Series of Autotaxin Inhibitors

Autotaxin (ATX) is a secreted enzyme playing a major role in the production of lysophosphatidic acid (LPA) in blood through hydrolysis of lysophosphatidyl choline (LPC). The ATX–LPA signaling axis arouses a high interest in the drug discovery industry as it has been implicated in several diseases including cancer, fibrotic diseases, and inflammation, among others. An imidazo­[1,2-<i>a</i>]­pyridine series of ATX inhibitors was identified out of a high-throughput screening (HTS). A cocrystal structure with one of these compounds and ATX revealed a novel binding mode with occupancy of the hydrophobic pocket and channel of ATX but no interaction with zinc ions of the catalytic site. Exploration of the structure–activity relationship led to compounds displaying high activity in biochemical and plasma assays, exemplified by compound <b>40</b>. Compound <b>40</b> was also able to decrease the plasma LPA levels upon oral administration to rats