title: Toluidinesulfonamide hypoxia-induced factor 1 inhibitors: alleviating drug-drug interactions through use of PubChem data and comparative molecular field analysis guided synthesis.
abstract: 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 PubChem database to develop a topomer CoMFA model that guided the design of novel sulfonamides with high selectivity for HIF-1 over CYP2C9 inhibition.
authors.affiliation: Elara Pharmaceuticals GmbH , Boxbergring 107, 69127 Heidelberg, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Wendt
authors.forename: Marcel
authors.initials: M
authors.lastname: Mulbaier
authors.forename: Sabine
authors.initials: S
authors.lastname: Wawro
authors.forename: Christoph
authors.initials: C
authors.lastname: Schultes
authors.forename: Jorge
authors.initials: J
authors.lastname: Alonso
authors.forename: Bernd
authors.initials: B
authors.lastname: Janssen
authors.forename: Joe
authors.initials: J
authors.lastname: Lewis
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D065729:Cytochrome P-450 CYP2C9; D016208:Databases, Factual; D015195:Drug Design; D004347:Drug Interactions; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008024:Ligands; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D014052:Toluidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D051793:Hypoxia-Inducible Factor 1; D008024:Ligands; D013449:Sulfonamides; D014052:Toluidines; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001189:Aryl Hydrocarbon Hydroxylases