Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile

Discovery of ((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone, PF-4254196, a CCR2 antagonist with an improved cardiovascular profile

We describe the systematic optimization, focused on the improvement of CV-TI, of a series of CCR2 antagonists. This work resulted in the identification of 10 (((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)meth...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2011-05, Vol.21 (9), p.2626-2630
Hauptverfasser: Hughes, Robert O, Rogier, D.J, Devraj, Rajesh, Zheng, Changsheng, Cao, Ganfeng, Feng, Hao, Xia, Michael, Anand, Rajan, Xing, Li, Glenn, Joseph, Zhang, Ke, Covington, Maryanne, Morton, Philip A, Hutzler, J. Matthew, Davis, John W., II, Scherle, Peggy, Baribaud, Fred, Bahinski, Anthony, Mo, Zun-Li, Newton, Robert, Metcalf, Brian, Xue, Chu-Biao
Format: Artikel
Sprache:eng
Schlagworte:
antagonists
Anti-Inflammatory Agents - chemistry
Anti-Inflammatory Agents - pharmacokinetics
Anti-Inflammatory Agents - pharmacology
Biological Assay
chemistry
Humans
Inhibitory Concentration 50
Microsomes - drug effects
Microsomes - metabolism
Models, Molecular
Molecular Structure
Piperazines - chemistry
Piperazines - pharmacokinetics
Piperazines - pharmacology
Protein Binding - drug effects
Pyridazines - chemistry
Pyridazines - pharmacokinetics
Pyridazines - pharmacology
Receptors, CCR2 - agonists
Receptors, CCR2 - blood
Structure-Activity Relationship
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Zusammenfassung:We describe the systematic optimization, focused on the improvement of CV-TI, of a series of CCR2 antagonists. This work resulted in the identification of 10 (((1S,3R)-1-isopropyl-3-((3S,4S)-3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone) which possessed a low projected human dose 35–45mg BID and a CV-TI=3800-fold.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.01.034