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
2011
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
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.
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