title: Discovery of acylurea isosteres of 2-acylaminothiadiazole in the azaxanthene series of glucocorticoid receptor agonists.
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.
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Hua
authors: H
authors: Gong
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Michael
authors: M
authors: Yang
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Zili
authors: Z
authors: Xiao
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Arthur M
authors: AM
authors: Doweyko
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Mark
authors: M
authors: Cunningham
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Jinhong
authors: J
authors: Wang
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Sium
authors: S
authors: Habte
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Deborah
authors: D
authors: Holloway
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Christine
authors: C
authors: Burke
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: David
authors: D
authors: Shuster
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Ling
authors: L
authors: Gao
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Julie
authors: J
authors: Carman
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: John E
authors: JE
authors: Somerville
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Steven G
authors: SG
authors: Nadler
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Luisa
authors: L
authors: Salter-Cid
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States.
authors: Joel C
authors: JC
authors: Barrish
authors: Department of Discovery Chemistry, Immunoscience, Bristol-Myers Squibb Company, Research and Development, Princeton, NJ 08543-4000, United States. Electronic address: David.Weinstein@bms.com.
authors: David S
authors: DS
authors: Weinstein
mesh_terms: D018360:Crystallography, X-Ray; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011965:Receptors, Glucocorticoid / Q000819:agonists*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology*; D014508:Urea / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D011965:Receptors, Glucocorticoid; D013830:Thiadiazoles; D014508:Urea
keywords: Acylurea; Glucocorticoid receptor; Imide; Isostere; Non-steroidal glucocorticoid receptor agonists