title: A new mode of mineralocorticoid receptor antagonism by a potent and selective nonsteroidal molecule.
abstract: Limitations of current steroidal mineralocorticoid receptor (MR) antagonists have stimulated the search for a new generation of molecules. We screened for novel nonsteroidal compounds and identified MR antagonists derived from the chemical class of dihydropyridines. Chemical optimization resulted in BR-4628, which displays high in vitro and in vivo MR potency as well as selectivity with respect to the other steroid hormone receptors and the L-type calcium channel. Biochemical studies demonstrated that BR-4628 forms complexes with MR that do not promote the recruitment of transcriptional co-regulators. Docking experiments, using the crystal structure of the MR ligand-binding domain in an agonist conformation, revealed that BR-4628 accommodates in the MR ligand-binding cavity differently in comparison with the classical steroidal MR antagonists. An alanine scanning mutagenesis approach, based on BR-4628 docking, allowed identifying its anchoring mode within the ligand-binding cavity. Altogether, we propose that BR-4628 is a bulky antagonist that inactivates MR through a passive mechanism. It represents the prototype of a new class of MR antagonists.
authors.affiliation: Department of Medicinal Chemistry, Bayer Schering Pharma AG, Global Drug Discovery, 42096 Wuppertal, Germany.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fagart
authors.forename: Alexander
authors.initials: A
authors.lastname: Hillisch
authors.forename: Jessica
authors.initials: J
authors.lastname: Huyet
authors.forename: Lars
authors.initials: L
authors.lastname: Bärfacker
authors.forename: Michel
authors.initials: M
authors.lastname: Fay
authors.forename: Ulrich
authors.initials: U
authors.lastname: Pleiss
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Pook
authors.forename: Stefan
authors.initials: S
authors.lastname: Schäfer
authors.forename: Marie-Edith
authors.initials: ME
authors.lastname: Rafestin-Oblin
authors.forename: Peter
authors.initials: P
authors.lastname: Kolkhof
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D016466:CHO Cells; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D004095:Dihydropyridines / Q000737:chemistry / Q000494:pharmacology*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008024:Ligands; D000451:Mineralocorticoid Receptor Antagonists; D020125:Mutation, Missense; D018161:Receptors, Mineralocorticoid / Q000235:genetics / Q000378:metabolism
chemical_list: D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D008024:Ligands; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid