Toluidinesulfonamide Hypoxia-Induced Factor 1 Inhibitors: Alleviating Drug-Drug Interactions through Use of PubChem Data and Comparative Molecular Field Analysis Guided Synthesis

Inhibitors of hypoxia-inducible factor 1 (HIF-1) represent promising anticancer therapeutics. We have identified a series of potent toluidinesulfonamide HIF-1 inhibitors. However, the series was threatened by a potential liability to inhibit CYP2C9 which could cause dangerous drug drug interactions when being coadministered with other drugs. We used structure activity data from the Pub Chem database to develop a topomer CoMFA model that guided the design of novel sulfonamides with high selectivity for HIF-1 over CYP2C9 inhibition.