title: Optimization of a series of quinazolinone-derived antagonists of CXCR3.
abstract: The evaluation of the CXCR3 antagonist AMG 487 in clinic trials was complicated due to the formation of an active metabolite. In this Letter, we will discuss the further optimization of the quinazolinone series that led to the discovery of compounds devoid of the formation of the active metabolite that was seen with AMG 487. In addition, these compounds also feature increased potency and good pharmacokinetic properties. We will also discuss the efficacy of the lead compound 34 in a mouse model of cellular recruitment induced by bleomycin.
authors.affiliation: Amgen Inc., 1120 Veterans Boulevard, South San Francisco, CA 94080, USA. jiwenl@amgen.com
authors.forename: Jiwen
authors.initials: J
authors.lastname: Liu
authors.forename: Zice
authors.initials: Z
authors.lastname: Fu
authors.forename: An-Rong
authors.initials: AR
authors.lastname: Li
authors.forename: Michael
authors.initials: M
authors.lastname: Johnson
authors.forename: Liusheng
authors.initials: L
authors.lastname: Zhu
authors.forename: Andrew
authors.initials: A
authors.lastname: Marcus
authors.forename: Jay
authors.initials: J
authors.lastname: Danao
authors.forename: Tim
authors.initials: T
authors.lastname: Sullivan
authors.forename: George
authors.initials: G
authors.lastname: Tonn
authors.forename: Tassie
authors.initials: T
authors.lastname: Collins
authors.forename: Julio
authors.initials: J
authors.lastname: Medina
mesh_terms: D000081:Acetamides / Q000494:pharmacology; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D002465:Cell Movement; D004285:Dogs; D000882:Haplorhini; D006801:Humans; D051379:Mice; D011744:Pyrimidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D052999:Quinazolinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D051381:Rats; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D000081:Acetamides; D000893:Anti-Inflammatory Agents; C541505:N-(1-(3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido(2,3-d)pyrimidin-2-yl)ethyl)-N-pyridin-3-ylmethyl-2-(4-trifluoromethoxyphenyl)acetamide; D011744:Pyrimidinones; D052999:Quinazolinones; D054367:Receptors, CXCR3; D013450:Sulfones