Discovery of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid diamides that increase CFTR mediated chloride transport

A series of 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid diamides that increase chloride transport in cells expressing mutant cystic fibrosis transmembrane conductance regulator (CFTR) protein has been identified from our compound library. Analoging efforts and the resulting structure–activity relationships uncovered are detailed. Compound potency was improved over 30-fold from the original lead, yielding several analogs with EC50 values below 10 nM in our cellular chloride transport assay.

Graphical abstractA series of compounds based on the 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid diamide core structure are reported as potent enhancers of CFTR mediated chloride transport.Figure optionsDownload full-size imageDownload as PowerPoint slide