Identification of spirooxindole and dibenzoxazepine motifs as potent mineralocorticoid receptor antagonists

• Published in: Bioorganic & medicinal chemistry Vol. 24; no. 6; pp. 1384 - 1391
• Main Authors: Lotesta, Stephen D., Marcus, Andrew P., Zheng, Yajun, Leftheris, Katerina, Noto, Paul B., Meng, Shi, Kandpal, Geeta, Chen, Guozhou, Zhou, Jing, McKeever, Brian, Bukhtiyarov, Yuri, Zhao, Yi, Lala, Deepak S., Singh, Suresh B., McGeehan, Gerard M.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 15.03.2016; Elsevier
• Subjects: Biochemistry & Molecular Biology; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Dibenzoxazepine; Dibenzoxazepines - chemical synthesis; Dibenzoxazepines - chemistry; Dibenzoxazepines - pharmacology; Dose-Response Relationship, Drug; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; Life Sciences & Biomedicine; Mineralocorticoid receptor; Mineralocorticoid Receptor Antagonists - chemical synthesis; Mineralocorticoid Receptor Antagonists - chemistry; Mineralocorticoid Receptor Antagonists - pharmacology; Models, Molecular; Molecular Structure; MR antagonist; Pharmacology & Pharmacy; Physical Sciences; Receptors, Mineralocorticoid - metabolism; Science & Technology; Spiro Compounds - chemical synthesis; Spiro Compounds - chemistry; Spiro Compounds - pharmacology; Spirooxindole; Structure-Activity Relationship; MR antagonist; Spirooxindole; Dibenzoxazepine; Mineralocorticoid receptor; MR; ARYL HALIDES; ESTERS; INHIBITORS; HYPERTENSION; DERIVATIVES; DISCOVERY; CORTISOL
• ISSN: 0968-0896; 1464-3391; 1464-3391
• DOI: 10.1016/j.bmc.2016.02.014

[Display omitted] 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.