Synthesis and evaluation of aniline headgroups for alkynyl thienopyrimidine dual EGFR/ErbB-2 kinase inhibitors.
Aniline 'headgroups' were synthesized and incorporated into an alkynyl thienopyrimidine series of EGFR and ErbB-2 inhibitors. Potent inhibition of enzyme activity and cellular proliferation was observed. In certain instances, protein binding was reduced and oral exposure was found to be somewhat improved relative to compounds containing the reference aniline.
Waterson
Alex G
AG
GlaxoSmithKline, Five Moore Drive, Research Triangle Park, NC 27709-3398, USA.
Petrov
Kimberly G
KG
Hornberger
Keith R
KR
Hubbard
Robert D
RD
Sammond
Douglas M
DM
Smith
Stephon C
SC
Dickson
Hamilton D
HD
Caferro
Thomas R
TR
Hinkle
Kevin W
KW
Stevens
Kirk L
KL
Dickerson
Scott H
SH
Rusnak
David W
DW
Spehar
Glenn M
GM
Wood
Edgar R
ER
Griffin
Robert J
RJ
Uehling
David E
DE
D000284:Administration, Oral; D000814:Aniline Compounds / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000379:methods; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D011743:Pyrimidines / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000814:Aniline Compounds; D066246:ErbB Receptors; D006131:Growth Inhibitors; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; C476003:thienopyrimidine; C512478:EGFR protein, human; C023650:aniline