CCR2 receptor antagonists: Optimization of biaryl sulfonamides to increase activity in whole blood

A series of biarylsulfonamides was identified as hCCR2 receptor antagonist but suffered from high plasma protein binding resulting in a >100 fold shift in activity in a functional GTPγS assay run in tandem in the presence and absence of human serum albumin. Introduction of an aryl amide with ethy...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2011-12, Vol.21 (24), p.7291-7294
Hauptverfasser:	Wang, Gren Z., Haile, Pamela A., Daniel, Tom, Belot, Benjamin, Viet, Andrew Q., Goodman, Krista B., Sha, Deyou, Dowdell, Sarah E., Varga, Norbert, Hong, Xuan, Chakravorty, Subhas, Webb, Christine, Cornejo, Carla, Olzinski, Alan, Bernard, Roberta, Evans, Christopher, Emmons, Amanda, Briand, Jacques, Chung, Chun-Wa, Quek, Ruben, Lee, Dennis, Gough, Peter J., Sehon, Clark A.
Format:	Artikel
Sprache:	eng
Schlagworte:	Administration, Oral Animals antagonists Biaryl sulfonamides Biological and medical sciences blood Bones, joints and connective tissue. Antiinflammatory agents CCR2 antagonists CCR2 knock-in mouse Gene Knock-In Techniques Guanosine 5'-O-(3-Thiotriphosphate) - blood HSA human serum albumin Humans MCP-1 Medical sciences Mice Mice, Inbred C57BL Pharmacology. Drug treatments protein binding Protein Binding - drug effects Rats receptors Receptors, CCR2 - antagonists & inhibitors Receptors, CCR2 - genetics Receptors, CCR2 - metabolism Serum Albumin - metabolism sulfonamides Sulfonamides - chemical synthesis Sulfonamides - chemistry Sulfonamides - pharmacokinetics Sulfonamides - pharmacology Thioglycolate induced peritonitis
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Zusammenfassung:	A series of biarylsulfonamides was identified as hCCR2 receptor antagonist but suffered from high plasma protein binding resulting in a >100 fold shift in activity in a functional GTPγS assay run in tandem in the presence and absence of human serum albumin. Introduction of an aryl amide with ethylenediamine linker led to compounds with reduced shifts and improved activity in whole blood.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2011.10.038