Discovery of an orally-bioavailable CC Chemokine Receptor 2 antagonist derived from an acyclic diaminoalcohol backbone

We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit...

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Published inBioorganic & medicinal chemistry letters Vol. 22; no. 9; pp. 3311 - 3316
Main Authors Carter, Percy H., Brown, Gregory D., King, Sarah R., Voss, Matthew E., Tebben, Andrew J., Cherney, Robert J., Mandlekar, Sandhya, Lo, Yvonne C., Yang, Gengjie, Miller, Persymphonie B., Scherle, Peggy A., Zhao, Qihong, Decicco, Carl P.
Format Journal Article
LanguageEnglish
Published Amsterdam Elsevier Ltd 01.05.2012
Elsevier
Subjects
Amino Alcohols - chemistry
Amino Alcohols - pharmacology
animal models
Animals
antagonists
beta chemokines
Biological and medical sciences
Biological Availability
CCR2
chemistry
Chemokine
General pharmacology
GPCR
Isostere
Medical sciences
Mice
Miscellaneous
Pharmacology. Drug treatments
Receptors, CCR2 - antagonists & inhibitors
Chemokine
GPCR
Isostere
CCR2
Aminoalcohol
G protein coupled receptor
Oral administration
CCR2 chemokine receptor
Antagonist
Bioavailability
Pharmacokinetics
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Summary:We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit nanomolar antagonists of CCR2. These studies led to the identification of 18, a compound that was suitable for studies in murine models of CCR2 activity. We describe an isostere-driven approach to improve upon a previously-described series of capped dipeptide antagonists of CC Chemokine Receptor 2 (CCR2). Modification of the substitution around the isostere was combined with additional changes in a distal aromatic substituent to provide single-digit nanomolar antagonists of CCR2. These studies led to the identification of 18, a compound that was suitable for studies in murine models of CCR2 activity.
Bibliography:http://dx.doi.org/10.1016/j.bmcl.2012.03.007
ObjectType-Article-1
SourceType-Scholarly Journals-1
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content type line 23
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2012.03.007