ABSTRACT
A novel, potent series of indole analogs were recently developed as MR antagonists, culminating in 14. This compound represents the first MR antagonist in this class of molecules, exhibiting picomolar binding affinity and in vivo blood pressure lowering at pharmaceutically relevant doses.
Subject(s)
Antihypertensive Agents/chemical synthesis , Indoles/chemical synthesis , Mineralocorticoid Receptor Antagonists , Sulfonamides/chemical synthesis , Animals , Antihypertensive Agents/chemistry , Antihypertensive Agents/pharmacology , Crystallography, X-Ray , Indoles/chemistry , Indoles/pharmacology , Models, Molecular , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
Benzopyran selective estrogen receptor beta agonist-1 (SERBA-1) shows potent, selective binding and agonist function in estrogen receptor beta (ERbeta) in vitro assays. X-ray crystal structures of SERBA-1 in ERalpha and beta help explain observed beta-selectivity of this ligand. SERBA-1 in vivo demonstrates involution of the ventral prostate in CD-1 mice (ERbeta effect), while having no effect on gonadal hormone levels (ERalpha effect) at 10x the efficacious dose, consistent with in vitro properties of this molecule.
