Discovery of a potent series of non-steroidal non α-trifluoromethyl carbinol glucocorticoid receptor agonists with reduced lipophilicity

A novel series of indazole non-steroidal glucocorticoid receptor agonist has been discovered. This series features a sulfonamide central core and meta amides which interact with the extended ligand binding domain. This series has produced some of the most potent and least lipophilic agonists of which we are aware such as 20a (NFκB pIC50 8.3 (100%), c log P 1.9). Certain analogues in this series also display evidence for modulated pharmacology.