γ-Lactams as glycinamide replacements in cyclohexane-based CC chemokine receptor 2 (CCR2) antagonists

We describe the design, synthesis, and evaluation, of γ-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists. We describe the design, synthesis, and evaluation, of γ-lactams as glycinamide replacements within a series of di- and trisubstituted cy...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 20; no. 8; pp. 2425 - 2430
Main Authors:	Cherney, Robert J., Mo, Ruowei, Meyer, Dayton T., Voss, Matthew E., Yang, Michael G., Santella, Joseph B., Duncia, John V., Lo, Yvonne C., Yang, Gengjie, Miller, Persymphonie B., Scherle, Peggy A., Zhao, Qihong, Mandlekar, Sandhya, Cvijic, Mary Ellen, Barrish, Joel C., Decicco, Carl P., Carter, Percy H.
Format:	Journal Article
Language:	English
Published:	Amsterdam Elsevier Ltd 15-04-2010 Elsevier
Subjects:	Animals Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents CCR2 CCR2 Antagonist Chemokine antagonist Chemotaxis - drug effects Cyclohexanes - chemistry Cyclohexanes - pharmacology Glycine - analogs & derivatives Glycine - chemistry GPCR Lactams - chemistry Medical sciences Mice Pharmacology. Drug treatments Receptors, CCR2 - antagonists & inhibitors γ-lactam CCR2 Antagonist GPCR Chemokine antagonist γ-lactam CCR2 Five membered ring Cyclohexane derivatives Intravenous administration Sulfone Nitrogen heterocycle Lactam Structure activity relation G protein coupled receptor Antagonist Chemical synthesis Dog Fissipedia Carnivora Aminoamide Rodentia Benzene derivatives Oral administration CCR2 chemokine receptor In vitro In vivo Vertebrata Metabolic stability Mammalia Mouse Animal Tertiary amine Affinity Carboxamide Fluorine Organic compounds Pharmacokinetics
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Summary:	We describe the design, synthesis, and evaluation, of γ-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists. We describe the design, synthesis, and evaluation, of γ-lactams as glycinamide replacements within a series of di- and trisubstituted cyclohexane CCR2 antagonists. The lactam-containing trisubstituted cyclohexanes proved to be more potent than the disubstituted analogs, as trisubstituted analog, lactam 13, displayed excellent activity (CCR2 binding IC 50 = 1.0 nM and chemotaxis IC 50 = 0.5 nM) and improved metabolic stability over its parent glycinamide.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2010.03.035