Tyrosine Kinase Inhibitors. 17. Irreversible Inhibitors of the Epidermal Growth Factor Receptor: 4-(Phenylamino)quinazoline- and 4-(Phenylamino)pyrido[3,2-d]pyrimidine-6-acrylamides Bearing Additional Solubilizing Functions
Abstract
4-Anilinoquinazoline- and 4-anilinopyrido[3,2-d]pyrimidine-6-acrylamides substituted with solubilizing 7-alkylamine or 7-alkoxyamine side chains were prepared by reaction of the corresponding 6-amines with acrylic acid or acrylic acid anhydrides. In the pyrido[3,2-d]pyrimidine series, the intermediate 6-amino-7-alkylamines were prepared from 7-bromo-6-fluoropyrido[3,2-d]pyrimidine via Stille coupling with the appropriate stannane under palladium(0) catalysis. This proved a versatile method for the introduction of cationic solubilizing side chains. The compounds were evaluated for their inhibition of phosphorylation of the isolated EGFR enzyme and for inhibition of EGF-stimulated autophosphorylation of EGFR in A431 cells and of heregulin-stimulated autophosphorylation of erbB2 in MDA-MB 453 cells. Quinazoline analogues with 7-alkoxyamine solubilizing groups were potent irreversible inhibitors of the isolated EGFR enzyme, with IC(50[app]) values from 2 to 4 nM, and potently inhibited both EGFR and erbB2 autophosphorylation in cells. 7-Alkylamino- and 7-alkoxyaminopyrido[3,2-d]pyrimidines were also irreversible inhibitors with equal or superior potency against the isolated enzyme but were less effective in the cellular autophosphorylation assays. Both quinazoline- and pyrido[3,2-d]pyrimidine-6-acrylamides bound at the ATP site alkylating cysteine 773, as shown by electrospray ionization mass spectrometry, and had similar rates of absorptive and secretory transport in Caco-2 cells. A comparison of two 7-propoxymorpholide analogues showed that the pyrido[3,2-d]pyrimidine-6-acrylamide had greater amide instability and higher acrylamide reactivity, being converted to glutathione adducts in cells more rapidly than the corresponding quinazoline. This difference may contribute to the observed lower cellular potency of the pyrido[3,2-d]pyrimidine-6-acrylamides. Selected compounds showed high in vivo activity against A431 xenografts on oral dosing, with the quinazolines being superior to the pyrido[3,2-d]pyrimidines. Overall, the quinazolines proved superior to previous analogues in terms of aqueous solubility, potency, and in vivo antitumor activity, and one example (CI 1033) has been selected for clinical evaluation.
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- Authors
- Smaill, J. B., Rewcastle, G. W., Loo, J. A., Greis, K. D., Chan, O. H., Reyner, E. L., Lipka, E., Showalter, H. D. H., Vincent, P. W., Elliott, W. L., & Denny, W. A.
- Affiliations
- University of Auckland (NZ)
- Venue
- Journal of Medicinal Chemistry
- Publisher
- American Chemical Society (ACS)
- Published
- 2000-03-14
- Volume
- 43
- Issue
- 7
- Pages
- 1380-1397
- ISSN
- 0022-2623 (ISSN-L)
- 1520-4804
- OpenAlex
- W2087023176
- Cited by
- 269
- References
- 15
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 4 · 2023: 9 · 2022: 5 · 2021: 7 · 2020: 8 · 2019: 6 · 2018: 8 · 2017: 16 · 2016: 12 · 2015: 12 · 2014: 9 · 2013: 12 · 2012: 12
- FWCI
- 14.77
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Medicinal Chemistry (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Physical Sciences › Chemistry › Organic Chemistry › Quinazolinone synthesis and applications
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Physical Sciences › Chemistry › Organic Chemistry › Synthesis and biological activity
- Keywords
- epidermal growth factor receptor, irreversible tyrosine kinase inhibitor, Stille coupling, palladium(0) catalysis, EGFR autophosphorylation, neuregulin-1, glutathione adducts
- MeSH terms
- Acrylamides, Animals, Antineoplastic Agents, Biological Transport, Drug Screening Assays, Antitumor, Enzyme Inhibitors, Humans, Mice, Nude, Morpholines, Neoplasm Transplantation, Phosphorylation, Pyrimidines, Quinazolines, Solubility, Transplantation, Heterologous, Tumor Cells, Cultured, Erb-b2 Receptor Tyrosine Kinases, Caco-2 Cells, Spectrometry, Mass, Electrospray Ionization, Mice, ErbB Receptors
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