Aryl sulfonamides commonly appear as recognition elements in ligands targeting protein kinases, ion channels and transcription factors and their unique hydrogen bonding and metabolic properties can often be exploited in drug design. During the discovery of novel pharmacological tools that inhibit TNNI3K, an anchoring hydrogen bond contact between an aryl sulfonamide and a gatekeeper threonine residue was observed that could be modulated through the addition of <i>para</i>-benzenesulfonamide substituents. A correlation between substituent electronic properties and TNNI3K affinity was delineated and exploited to generate selective inhibitors used to define the role of TNNI3K in cardiac biology. The observed electronic substituent effect signifies a fundamental relationship useful for optimization of sulfonamide protein-ligand interactions. Separately, while investigating a series of TRPV4 antagonists, we characterized the unique metabolic fate of electron-deficient aryl sulfonamides and rationally optimized the pharmacokinetics of the series by improving both clearance and volume of distribution through judicious selection of the aryl sulfonamide moiety. The electronic nature and conformational features of the aryl sulfonamide and consequent impact on metabolism and distribution were elucidated and used in the design of GSK3527497, a novel TRPV4 antagonist drug candidate.

Sulfonamides in the design of pharmacological tools and drug candidates

ACS Fall 2020 Virtual Meeting

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