Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors.
A novel class of pyrrolidinyl-acetyleneic thieno[3,2-d]pyrimidines has been identified which potently inhibit the EGFR and ErbB-2 receptor tyrosine kinases. Synthetic modifications of the pyrrolidine carbamate moiety result in a range of effects on enzyme and cellular potency. In addition, the impact of the absolute stereochemical configuration on cellular potency and oral mouse pharmacokinetics is described.
Stevens
Kirk L
KL
Department of Oncology Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA. Kirk.L.Stevens@GSK.com
Alligood
Krystal J
KJ
Alberti
Jennifer G Badiang
JG
Caferro
Thomas R
TR
Chamberlain
Stanley D
SD
Dickerson
Scott H
SH
Dickson
Hamilton D
HD
Emerson
Holly K
HK
Griffin
Robert J
RJ
Hubbard
Robert D
RD
Keith
Barry R
BR
Mullin
Robert J
RJ
Petrov
Kimberly G
KG
Gerding
Roseanne M
RM
Reno
Michael J
MJ
Rheault
Tara R
TR
Rusnak
David W
DW
Sammond
Douglas M
DM
Smith
Stephon C
SC
Uehling
David E
DE
Waterson
Alex G
AG
Wood
Edgar R
ER
D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D051379:Mice; D010599:Pharmacokinetics; D011743:Pyrimidines / Q000138:chemical synthesis / Q000494:pharmacology*; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D011743:Pyrimidines; D011759:Pyrrolidines; D018719:Erb-b2 Receptor Tyrosine Kinases; C032519:pyrrolidine