title: Discovery of 4-amino-5,6-biaryl-furo[2,3-d]pyrimidines as inhibitors of Lck: development of an expedient and divergent synthetic route and preliminary SAR.
abstract: 4-Amino-5,6-biaryl-furo[2,3-d]pyrimidines were identified as potent non-selective inhibitors of Lck. A novel, divergent, and practical synthetic route was developed to access derivatives from bifunctional intermediates. Lead optimization was guided by X-ray crystallographic data, and preliminary SAR led to the identification of compounds with improved cellular potency and selectivity.
authors.affiliation: Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA. edimauro@amgen.com
authors.forename: Erin F
authors.initials: EF
authors.lastname: DiMauro
authors.forename: John
authors.initials: J
authors.lastname: Newcomb
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Nunes
authors.forename: Jean E
authors.initials: JE
authors.lastname: Bemis
authors.forename: Christina
authors.initials: C
authors.lastname: Boucher
authors.forename: John L
authors.initials: JL
authors.lastname: Buchanan
authors.forename: William H
authors.initials: WH
authors.lastname: Buckner
authors.forename: Alan
authors.initials: A
authors.lastname: Cheng
authors.forename: Theodore
authors.initials: T
authors.lastname: Faust
authors.forename: Faye
authors.initials: F
authors.lastname: Hsieh
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.forename: Josie H
authors.initials: JH
authors.lastname: Lee
authors.forename: Teresa L
authors.initials: TL
authors.lastname: Marshall
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Martin
authors.forename: David C
authors.initials: DC
authors.lastname: McGowan
authors.forename: Stephen
authors.initials: S
authors.lastname: Schneider
authors.forename: Susan M
authors.initials: SM
authors.lastname: Turci
authors.forename: Ryan D
authors.initials: RD
authors.lastname: White
authors.forename: Xiaotian
authors.initials: X
authors.lastname: Zhu
mesh_terms: D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis; D006801:Humans; D020128:Inhibitory Concentration 50; D007376:Interleukin-2 / Q000378:metabolism; D007959:Lymphocyte Culture Test, Mixed; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000037:antagonists & inhibitors*; D008214:Lymphocytes / Q000187:drug effects; D010599:Pharmacokinetics; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000493:pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000893:Anti-Inflammatory Agents; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)