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 |
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| Authors: | 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 Scherle Peggy Baribaud Fred Bahinski Anthony Mo Zun-Li Newton Robert Metcalf Brian Xue Chu-Biao |
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| Institution: | a Pfizer Global Research and Development, Chesterfield Parkway West, St. Louis, MO 63017, USA
b Incyte Corporation, Experimental Station, Wilmington, DE 19880, USA |
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| Abstract: | 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 35-45 mg BID and a CV-TI = 3800-fold. |
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| Keywords: | CCR2 antagonist hERG hERG homology model |
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