Discovery of novel oxazolidinedione derivatives as potent and selective mineralocorticoid receptor antagonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 23; no. 15; pp. 4388 - 4392
• Main Authors: Yang, Christine, Shen, Hong C., Wu, Zhicai, Chu, Hong D., Cox, Jason M., Balsells, Jaume, Crespo, Alejandro, Brown, Patricia, Zamlynny, Beata, Wiltsie, Judyann, Clemas, Joseph, Gibson, Jack, Contino, Lisa, Lisnock, JeanMarie, Zhou, Gaochao, Garcia-Calvo, Margarita, Bateman, Tom, Xu, Ling, Tong, Xinchun, Crook, Martin, Sinclair, Peter
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier Ltd 01.08.2013; Elsevier
• Subjects: Animals; antagonists; Binding Sites; Chemistry; Chemistry, Medicinal; Chemistry, Organic; Drug Evaluation, Preclinical; Half-Life; Humans; Hypertension; Life Sciences & Biomedicine; Microsomes - metabolism; Mineralocorticoid receptor antagonist; Mineralocorticoid Receptor Antagonists - chemical synthesis; Mineralocorticoid Receptor Antagonists - chemistry; Mineralocorticoid Receptor Antagonists - pharmacokinetics; mineralocorticoid receptors; Molecular Docking Simulation; Oxazoles - chemical synthesis; Oxazoles - chemistry; Oxazoles - pharmacokinetics; pharmacokinetics; Pharmacology & Pharmacy; Physical Sciences; Protein Structure, Tertiary; Rats; Receptors, Mineralocorticoid - chemistry; Receptors, Mineralocorticoid - metabolism; Science & Technology; Structure-Activity Relationship; structure-activity relationships; Hypertension; Mineralocorticoid receptor antagonist; LEFT-VENTRICULAR DYSFUNCTION; RESISTANT HYPERTENSION; SPIRONOLACTONE; BIOLOGY; ALDOSTERONE BLOCKER; CONGESTIVE-HEART-FAILURE; EPLERENONE; INHIBITOR
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2013.05.077

Novel oxazolidinedione analogs were discovered as potent and selective mineralocorticoid receptor (MR) antagonists. Structure–activity relationship (SAR) studies were focused on improving the potency and microsomal stability. Selected compounds demonstrated excellent MR activity, reasonable nuclear hormone receptor selectivity, and acceptable rat pharmacokinetics.