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

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

doi:10.1016/j.bmcl.2014.06.010

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. Epub 2014 Jun 13.

Authors

Hua Gong¹, Michael Yang¹, Zili Xiao¹, Arthur M Doweyko¹, Mark Cunningham¹, Jinhong Wang¹, Sium Habte¹, Deborah Holloway¹, Christine Burke¹, David Shuster¹, Ling Gao¹, Julie Carman¹, John E Somerville¹, Steven G Nadler¹, Luisa Salter-Cid¹, Joel C Barrish¹, David S Weinstein²

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.

MeSH terms

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
Models, Molecular
Molecular Structure
Receptors, Glucocorticoid / agonists*
Stereoisomerism
Structure-Activity Relationship
Thiadiazoles / chemistry
Thiadiazoles / pharmacology*
Urea / analogs & derivatives
Urea / chemistry
Urea / pharmacology*

Substances

Heterocyclic Compounds, 3-Ring
Receptors, Glucocorticoid
Thiadiazoles
Urea