title: 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.
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 35-45mg BID and a CV-TI=3800-fold.
authors.affiliation: Pfizer Global Research and Development, Chesterfield Parkway West, St. Louis, MO 63017, USA. robert.o.hughes@pfizer.com
authors.forename: Robert O
authors.initials: RO
authors.lastname: Hughes
authors.forename: D J
authors.initials: DJ
authors.lastname: Rogier
authors.forename: Rajesh
authors.initials: R
authors.lastname: Devraj
authors.forename: Changsheng
authors.initials: C
authors.lastname: Zheng
authors.forename: Ganfeng
authors.initials: G
authors.lastname: Cao
authors.forename: Hao
authors.initials: H
authors.lastname: Feng
authors.forename: Michael
authors.initials: M
authors.lastname: Xia
authors.forename: Rajan
authors.initials: R
authors.lastname: Anand
authors.forename: Li
authors.initials: L
authors.lastname: Xing
authors.forename: Joseph
authors.initials: J
authors.lastname: Glenn
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.forename: Maryanne
authors.initials: M
authors.lastname: Covington
authors.forename: Philip A
authors.initials: PA
authors.lastname: Morton
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Hutzler
authors.forename: John W
authors.initials: JW
authors.lastname: Davis
authors.forename: Peggy
authors.initials: P
authors.lastname: Scherle
authors.forename: Fred
authors.initials: F
authors.lastname: Baribaud
authors.forename: Anthony
authors.initials: A
authors.lastname: Bahinski
authors.forename: Zun-Li
authors.initials: ZL
authors.lastname: Mo
authors.forename: Robert
authors.initials: R
authors.lastname: Newton
authors.forename: Brian
authors.initials: B
authors.lastname: Metcalf
authors.forename: Chu-Biao
authors.initials: CB
authors.lastname: Xue
mesh_terms: D000893:Anti-Inflammatory Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001681:Biological Assay; D006801:Humans; D020128:Inhibitory Concentration 50; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D010879:Piperazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011724:Pyridazines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D054390:Receptors, CCR2 / Q000819:agonists* / Q000097:blood; D013329:Structure-Activity Relationship
chemical_list: C560206:((1-isopropyl-3-(3-methoxy-tetrahydro-2H-pyran-4-ylamino)cyclopentyl)(4-(5-(trifluoromethyl)pyridazin-3-yl)piperazin-1-yl)methanone); D000893:Anti-Inflammatory Agents; D010879:Piperazines; D011724:Pyridazines; D054390:Receptors, CCR2