Discovery of N-propylurea 3-benzylpiperidines as selective CC chemokine receptor-3 (CCR3) antagonists

• Published in: Bioorganic & medicinal chemistry letters 2004-04, Vol.14 (7), p.1645-1649
• Main Authors: Varnes, Jeffrey G, Gardner, Daniel S, Santella, Joseph B, Duncia, John V, Estrella, Melissa, Watson, Paul S, Clark, Cheryl M, Ko, Soo S, Welch, Patricia, Covington, Maryanne, Stowell, Nicole, Wadman, Eric, Davies, Paul, Solomon, Kimberley, Newton, Robert C, Trainor, George L, Decicco, Carl P, Wacker, Dean A
• Format: Article
• Language: English
• Subjects: Allergic diseases; Animals; Biological and medical sciences; Cattle; CHO Cells; Cricetinae; Immunopathology; Medical sciences; Pharmacology. Drug treatments; Piperidines - chemistry; Piperidines - metabolism; Protein Binding - physiology; Receptors, CCR3; Receptors, Chemokine - antagonists & inhibitors; Receptors, Chemokine - metabolism; Respiratory and ent allergic diseases; Respiratory system; Urea - analogs & derivatives; Urea - chemistry; Urea - metabolism
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2004.01.059

The discovery of novel and selective small molecule antagonists of the CC Chemokine Receptor-3 (CCR3) is presented. Simple conversion from a 4- to 3-benzylpiperidine gave improved selectivity for CCR3 over the serotonin 5HT 2A receptor. Chiral resolution and exploration of mono- and disubstitution of the N-propylurea resulted in several 3-benzylpiperidine N-propylureas with CCR3 binding IC 50s under 5 nM. Data from in vitro calcium mobilization and chemotaxis assays for these compounds ranged from high picomolar to low nanomolar EC 50s and correlated well with antagonist binding IC 50s. Graphic