Dual EGFR/ErbB-2 inhibitors from novel pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines.
A novel class of substituted pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines has been identified that are potent and selective inhibitors of both EGFR/ErbB-2 receptor tyrosine kinases. The inhibitors are found to display a range of enzyme and cellular potency and also to display a varying level of covalent modification of the kinase targets. Selected molecules, including compound 15h, were found to be potent in enzymatic and cellular assays while also demonstrating exposure in the mouse from an oral dose.
Hubbard
Robert D
RD
GlaxoSmithKline Research & Development, Research Triangle Park, NC 27709-3398, USA.
Dickerson
Scott H
SH
Emerson
Holly K
HK
Griffin
Robert J
RJ
Reno
Michael J
MJ
Hornberger
Keith R
KR
Rusnak
David W
DW
Wood
Edgar R
ER
Uehling
David E
DE
Waterson
Alex G
AG
D000818:Animals; D002460:Cell Line; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D051379:Mice; D011485:Protein Binding; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D066246:ErbB Receptors; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases