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.
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.
DiMauro
Erin F
EF
Department of Medicinal Chemistry, Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA. edimauro@amgen.com
Newcomb
John
J
Nunes
Joseph J
JJ
Bemis
Jean E
JE
Boucher
Christina
C
Buchanan
John L
JL
Buckner
William H
WH
Cheng
Alan
A
Faust
Theodore
T
Hsieh
Faye
F
Huang
Xin
X
Lee
Josie H
JH
Marshall
Teresa L
TL
Martin
Matthew W
MW
McGowan
David C
DC
Schneider
Stephen
S
Turci
Susan M
SM
White
Ryan D
RD
Zhu
Xiaotian
X
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
D000893:Anti-Inflammatory Agents; D007376:Interleukin-2; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck)