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rdf:type |
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lifeskim:mentions |
umls-concept:C0021467,
umls-concept:C0021469,
umls-concept:C0026837,
umls-concept:C0184512,
umls-concept:C0231491,
umls-concept:C0231517,
umls-concept:C0439284,
umls-concept:C0439596,
umls-concept:C1326501,
umls-concept:C1413189,
umls-concept:C1527148,
umls-concept:C1705542,
umls-concept:C1880355,
umls-concept:C2353870
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pubmed:issue |
2
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pubmed:dateCreated |
2008-1-21
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pubmed:abstractText |
Conformational analysis of trans-1,2-disubstituted cyclohexane CCR3 antagonist 2 revealed that the cyclohexane linker could be replaced by an acyclic syn-alpha-methyl-beta-hydroxypropyl linker. Synthesis and biological evaluation of mono- and disubstituted propyl linkers support this conformational correlation. It was also found that the alpha-methyl group to the urea lowered protein binding and that the beta-hydroxyl group lowered affinity for CYP2D6. Ab initio calculations show that the alpha-methyl group governs the spatial orientation of three key functionalities within the molecule. alpha-Methyl-beta-hydroxypropyl urea 31 with a chemotaxis IC(50)=38 pM for eosinophils was chosen to enter clinical development for the treatment of asthma.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
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|
pubmed:status |
MEDLINE
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pubmed:month |
Jan
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pubmed:issn |
1464-3405
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|
pubmed:author |
pubmed-author:CarterPercy HPH,
pubmed-author:DaviesPaulP,
pubmed-author:DeLuccaGeorge VGV,
pubmed-author:DeciccoCarl PCP,
pubmed-author:DunciaJohn VJV,
pubmed-author:GardnerDaniel SDS,
pubmed-author:GradenDani MDM,
pubmed-author:KarivIlonaI,
pubmed-author:KoSoo SSS,
pubmed-author:MandlekarSandhyaS,
pubmed-author:ReddyPrabhakarP,
pubmed-author:SantellaJoseph BJB3rd,
pubmed-author:ShiChongshengC,
pubmed-author:SolomonKimberly AKA,
pubmed-author:TebbenAndrew JAJ,
pubmed-author:WackerDean ADA,
pubmed-author:WadmanEric AEA,
pubmed-author:WatsonPaul SPS,
pubmed-author:WelchPatricia KPK,
pubmed-author:YaoWenqingW,
pubmed-author:YeleswaramSwamyS
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|
pubmed:issnType |
Electronic
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pubmed:day |
15
|
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pubmed:volume |
18
|
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pubmed:owner |
NLM
|
|
pubmed:authorsComplete |
Y
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pubmed:pagination |
576-85
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pubmed:meshHeading |
pubmed-meshheading:18096386-Administration, Oral,
pubmed-meshheading:18096386-Animals,
pubmed-meshheading:18096386-Chemotaxis, Leukocyte,
pubmed-meshheading:18096386-Cytochrome P-450 Enzyme System,
pubmed-meshheading:18096386-Dogs,
pubmed-meshheading:18096386-Eosinophils,
pubmed-meshheading:18096386-Hydrogen Bonding,
pubmed-meshheading:18096386-Mice,
pubmed-meshheading:18096386-Molecular Conformation,
pubmed-meshheading:18096386-Piperidines,
pubmed-meshheading:18096386-Rats,
pubmed-meshheading:18096386-Receptors, CCR3,
pubmed-meshheading:18096386-Structure-Activity Relationship,
pubmed-meshheading:18096386-Urea
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pubmed:year |
2008
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pubmed:articleTitle |
From rigid cyclic templates to conformationally stabilized acyclic scaffolds. Part I: the discovery of CCR3 antagonist development candidate BMS-639623 with picomolar inhibition potency against eosinophil chemotaxis.
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pubmed:affiliation |
Bristol-Myers Squibb Company, R&D, PO Box 4000, Princeton, NJ 08543-4000, USA.
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pubmed:publicationType |
Journal Article
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