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.
GlaxoSmithKline Research & Development, Research Triangle Park, NC 27709-3398, USA.
Robert D
RD
Hubbard
Scott H
SH
Dickerson
Holly K
HK
Emerson
Robert J
RJ
Griffin
Michael J
MJ
Reno
Keith R
KR
Hornberger
David W
DW
Rusnak
Edgar R
ER
Wood
David E
DE
Uehling
Alex G
AG
Waterson
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