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Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors |
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| Authors: | Kirk L Stevens Krystal J Alligood Jennifer G Badiang Alberti Thomas R Caferro Stanley D Chamberlain Scott H Dickerson Hamilton D Dickson Holly K Emerson Robert J Griffin Robert D Hubbard Barry R Keith Robert J Mullin Kimberly G Petrov Roseanne M Gerding Michael J Reno Tara R Rheault David W Rusnak Douglas M Sammond Stephon C Smith David E Uehling Edgar R Wood |
| Institution: | 1. Department of Oncology Medicinal Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA;2. Department of Oncology Biology, GlaxoSmithKline, Research Triangle Park, NC 27709, USA;3. Department of Computational and Structural Chemistry, GlaxoSmithKline, Research Triangle Park, NC 27709, USA;4. Department of Drug Metabolism and Pharmacokinetics, GlaxoSmithKline, Research Triangle Park, NC 27709, USA;5. Department of Biochemical and Cellular Targets, GlaxoSmithKline, Research Triangle Park, NC 27709, USA |
| Abstract: | A novel class of pyrrolidinyl-acetyleneic thieno3,2-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. |
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