title: Identification of spirooxindole and dibenzoxazepine motifs as potent mineralocorticoid receptor antagonists.
abstract: Mineralocorticoid receptor (MR) antagonists continue to be a prevalent area of research in the pharmaceutical industry. Herein we report the discovery of various spirooxindole and dibenzoxazepine constructs as potent MR antagonists. SAR analysis of our spirooxindole hit led to highly potent compounds containing polar solubilizing groups, which interact with the helix-11 region of the MR ligand binding domain (LBD). Various dibenzoxazepine moieties were also prepared in an effort to replace a known dibenzoxepane system which interacts with the hydrophobic region of the MR LBD. In addition, an X-ray crystal structure was obtained from a highly potent compound which was shown to exhibit both partial agonist and antagonist modes of action against MR.
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States. Electronic address: slotesta@vitaerx.com.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Lotesta
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Marcus
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Yajun
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Katerina
authors.initials: K
authors.lastname: Leftheris
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Paul B
authors.initials: PB
authors.lastname: Noto
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Shi
authors.initials: S
authors.lastname: Meng
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Geeta
authors.initials: G
authors.lastname: Kandpal
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Guozhou
authors.initials: G
authors.lastname: Chen
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Brian
authors.initials: B
authors.lastname: McKeever
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Bukhtiyarov
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Deepak S
authors.initials: DS
authors.lastname: Lala
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Singh
authors.affiliation: Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, United States.
authors.forename: Gerard M
authors.initials: GM
authors.lastname: McGeehan
mesh_terms: D018360:Crystallography, X-Ray; D003989:Dibenzoxazepines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000451:Mineralocorticoid Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D018161:Receptors, Mineralocorticoid / Q000378:metabolism*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D003989:Dibenzoxazepines; D007211:Indoles; D000451:Mineralocorticoid Receptor Antagonists; D018161:Receptors, Mineralocorticoid; D013141:Spiro Compounds
keywords: Dibenzoxazepine; MR; MR antagonist; Mineralocorticoid receptor; Spirooxindole