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

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3268-73. doi: 10.1016/j.bmcl.2014.06.010.

Hua Gong ¹, Michael Yang ¹, Zili Xiao ¹, Arthur M Doweyko ¹, Mark Cunningham ¹, Jinhong Wang ¹, Sium Habte ¹, Deborah Holloway ¹, Christine Burke ¹, David Shuster ¹, Ling Gao ¹, Julie Carman ¹, John E Somerville ¹, Steven G Nadler ¹, Luisa Salter-Cid ¹, Joel C Barrish ¹, David S Weinstein ²

Affiliations

1 Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
2 Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States. Electronic address: David.Weinstein@bms.com.

PMID: 24980053 DOI: 10.1016/j.bmcl.2014.06.010

Abstract

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.

Keywords

Acylurea; Glucocorticoid receptor; Imide; Isostere; Non-steroidal glucocorticoid receptor agonists.

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