Discovery of acylurea isosteres of 2-acylaminothiadiazole in the azaxanthene series of glucocorticoid receptor agonists

• Published in: Bioorganic & medicinal chemistry letters Vol. 24; no. 15; pp. 3268 - 3273
• Main Authors: Gong, Hua, Yang, Michael, Xiao, Zili, Doweyko, Arthur M., Cunningham, Mark, Wang, Jinhong, Habte, Sium, Holloway, Deborah, Burke, Christine, Shuster, David, Gao, Ling, Carman, Julie, Somerville, John E., Nadler, Steven G., Salter-Cid, Luisa, Barrish, Joel C., Weinstein, David S.
• Format: Journal Article
• Language: English
• Published: OXFORD Elsevier 01.08.2014
• Subjects: Chemistry; Chemistry, Medicinal; Chemistry, Organic; Crystallography, X-Ray; Dose-Response Relationship, Drug; Drug Discovery; Heterocyclic Compounds, 3-Ring - chemical synthesis; Heterocyclic Compounds, 3-Ring - chemistry; Heterocyclic Compounds, 3-Ring - pharmacology; Humans; Life Sciences & Biomedicine; Models, Molecular; Molecular Structure; Pharmacology & Pharmacy; Physical Sciences; Receptors, Glucocorticoid - agonists; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Thiadiazoles - chemistry; Thiadiazoles - pharmacology; Urea - analogs & derivatives; Urea - chemistry; Urea - pharmacology; Imide; Isostere; Acylurea; Non-steroidal glucocorticoid receptor agonists; MODULATORS; Glucocorticoid receptor; MECHANISMS
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2014.06.010

Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described. (C) 2014 Elsevier Ltd. All rights reserved.