Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors

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; Alex G. Waterson; Edgar R. Wood

doi:10.1016/j.bmcl.2008.11.023

Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors

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

Alex G. Waterson, Edgar R. Wood

Cooperative Programs for the Advancement of Earth System Science

GlaxoSmithKline

Research output: Contribution to journal › Article › peer-review

22 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	21-26
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	19
Issue number	1
DOIs	https://doi.org/10.1016/j.bmcl.2008.11.023
State	Published - Jan 1 2009

Keywords

EGFR
Epidermal growth factor receptor
ErbB-2
Inhibitor
Proline
Thieno[3,2-d]pyrimidines

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10.1016/j.bmcl.2008.11.023

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Stevens, K. L., Alligood, K. J., Alberti, J. G. B., Caferro, T. R., Chamberlain, S. D., Dickerson, S. H., Dickson, H. D., Emerson, H. K., Griffin, R. J., Hubbard, R. D., Keith, B. R., Mullin, R. J., Petrov, K. G., Gerding, R. M., Reno, M. J., Rheault, T. R., Rusnak, D. W., Sammond, D. M., Smith, S. C., ... Wood, E. R. (2009). Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors. Bioorganic and Medicinal Chemistry Letters, 19(1), 21-26. https://doi.org/10.1016/j.bmcl.2008.11.023

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title = "Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors",

abstract = "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.",

keywords = "EGFR, Epidermal growth factor receptor, ErbB-2, Inhibitor, Proline, Thieno[3,2-d]pyrimidines",

author = "Stevens, \{Kirk L.\} and Alligood, \{Krystal J.\} and Alberti, \{Jennifer G.Badiang\} and Caferro, \{Thomas R.\} and Chamberlain, \{Stanley D.\} and Dickerson, \{Scott H.\} and Dickson, \{Hamilton D.\} and Emerson, \{Holly K.\} and Griffin, \{Robert J.\} and Hubbard, \{Robert D.\} and Keith, \{Barry R.\} and Mullin, \{Robert J.\} and Petrov, \{Kimberly G.\} and Gerding, \{Roseanne M.\} and Reno, \{Michael J.\} and Rheault, \{Tara R.\} and Rusnak, \{David W.\} and Sammond, \{Douglas M.\} and Smith, \{Stephon C.\} and Uehling, \{David E.\} and Waterson, \{Alex G.\} and Wood, \{Edgar R.\}",

year = "2009",

month = jan,

day = "1",

doi = "10.1016/j.bmcl.2008.11.023",

language = "English",

volume = "19",

pages = "21--26",

journal = "Bioorganic and Medicinal Chemistry Letters",

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Stevens, KL, Alligood, KJ, Alberti, JGB, Caferro, TR, Chamberlain, SD, Dickerson, SH, Dickson, HD, Emerson, HK, Griffin, RJ, Hubbard, RD, Keith, BR, Mullin, RJ, Petrov, KG, Gerding, RM, Reno, MJ, Rheault, TR, Rusnak, DW, Sammond, DM, Smith, SC, Uehling, DE, Waterson, AG & Wood, ER 2009, 'Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 19, no. 1, pp. 21-26. https://doi.org/10.1016/j.bmcl.2008.11.023

TY - JOUR

T1 - Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors

AU - Stevens, Kirk L.

AU - Alligood, Krystal J.

AU - Alberti, Jennifer G.Badiang

AU - Caferro, Thomas R.

AU - Chamberlain, Stanley D.

AU - Dickerson, Scott H.

AU - Dickson, Hamilton D.

AU - Emerson, Holly K.

AU - Griffin, Robert J.

AU - Hubbard, Robert D.

AU - Keith, Barry R.

AU - Mullin, Robert J.

AU - Petrov, Kimberly G.

AU - Gerding, Roseanne M.

AU - Reno, Michael J.

AU - Rheault, Tara R.

AU - Rusnak, David W.

AU - Sammond, Douglas M.

AU - Smith, Stephon C.

AU - Uehling, David E.

AU - Waterson, Alex G.

AU - Wood, Edgar R.

PY - 2009/1/1

Y1 - 2009/1/1

N2 - 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.

AB - 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.

KW - EGFR

KW - Epidermal growth factor receptor

KW - ErbB-2

KW - Inhibitor

KW - Proline

KW - Thieno[3,2-d]pyrimidines

UR - https://www.scopus.com/pages/publications/57749096199

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DO - 10.1016/j.bmcl.2008.11.023

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AN - SCOPUS:57749096199

SN - 0960-894X

VL - 19

SP - 21

EP - 26

JO - Bioorganic and Medicinal Chemistry Letters

JF - Bioorganic and Medicinal Chemistry Letters

IS - 1

ER -

Synthesis and stereochemical effects of pyrrolidinyl-acetylenic thieno[3,2-d]pyrimidines as EGFR and ErbB-2 inhibitors

Abstract

Keywords

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