title: Discovery of potent and specific CXCR3 antagonists.
abstract: The optimization of a series of 8-aza-quinazolinone analogs for antagonist activity against the CXCR3 receptor is reported. Compounds were optimized to avoid the formation of active metabolites and time-dependent-inhibitors of CYP3A4. In addition, antagonists showed potent against CXCR3 activity in whole blood and optimized to avoid activity in the chromosomal aberration assay. Compound 25 was identified as having the optimal balance of CXCR3 activity and pharmacokinetic properties across multiple pre-clinical species, which are reported herein.
authors: Amgen Inc., 1120 Veterans Boulevard, ASF2-3, South San Francisco, CA 94080, USA. xiaoqic@amgen.com
authors: Xiaoqi
authors: X
authors: Chen
authors: Jeff
authors: J
authors: Mihalic
authors: Jeff
authors: J
authors: Deignan
authors: Darin J
authors: DJ
authors: Gustin
authors: Jason
authors: J
authors: Duquette
authors: Xiaohui
authors: X
authors: Du
authors: Johann
authors: J
authors: Chan
authors: Zice
authors: Z
authors: Fu
authors: Michael
authors: M
authors: Johnson
authors: An-Rong
authors: AR
authors: Li
authors: Kirk
authors: K
authors: Henne
authors: Tim
authors: T
authors: Sullivan
authors: Bryan
authors: B
authors: Lemon
authors: Ji
authors: J
authors: Ma
authors: Shichang
authors: S
authors: Miao
authors: George
authors: G
authors: Tonn
authors: Tassie
authors: T
authors: Collins
authors: Julio C
authors: JC
authors: Medina
mesh_terms: D000818:Animals; D001761:Bleomycin / Q000633:toxicity; D002869:Chromosome Aberrations; D051544:Cytochrome P-450 CYP3A; D065692:Cytochrome P-450 CYP3A Inhibitors; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007249:Inflammation; D020128:Inhibitory Concentration 50; D007962:Leukocytes / Q000187:drug effects; D008252:Macaca fascicularis; D051379:Mice; D008956:Models, Chemical; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D052999:Quinazolinones / Q000138:chemical synthesis* / Q000494:pharmacology; D054367:Receptors, CXCR3 / Q000037:antagonists & inhibitors*; D013997:Time Factors
chemical_list: C573851:8-aza-quinazolinone; D065692:Cytochrome P-450 CYP3A Inhibitors; D011799:Quinazolines; D052999:Quinazolinones; D054367:Receptors, CXCR3; D001761:Bleomycin; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human