N⁴-Aryl-6-substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines As Receptor Tyrosine Kinase Inhibitors

Overview

Journal Bioorg Med Chem

Specialties Biochemistry
Chemistry

Date 2011 Dec 30

PMID 22204741

Citations 3

Authors

Aleem Gangjee

Sonali Kurup

Michael A Ihnat

Jessica E Thorpe

Bryan Disch

Affiliations

Soon will be listed here.

Abstract

Six novel N(4)-substitutedphenyl-6-substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamines were synthesized as multiple receptor tyrosine kinase (RTK) inhibitors and antitumor agents. An improvement in the inhibitory potency against epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor 1 (VEGFR-1) and vascular endothelial growth factor receptor 2 (VEGFR-2) assays and in the A431 cellular proliferation assay was observed for compounds 8-13 over the previously reported 5-7. Three compounds (8, 9 and 13) demonstrated potent, multiple RTK inhibition and were more potent or equipotent compared to the lead compounds 5 and 7 and the standard compounds. Compounds 10 and 12 showed potent inhibition of VEGFR-2 over EGFR, platelet-derived growth factor receptor-β (PDGFR-β) and VEGFR-1. The results indicate that the RTK inhibitory profile could be modulated with slight variations to the N(4)-aryl-6-substitutedphenylmethyl-7H-pyrrolo[2,3-d]pyrimidine-2,4-diamino scaffold.

Citing Articles

A Review on Fused Pyrimidine Systems as EGFR Inhibitors and Their Structure-Activity Relationship.

Yadav T, Shaikh G, Kumar M, Chintamaneni M, Yc M Front Chem. 2022; 10:861288.

PMID: 35769445 PMC: 9234326. DOI: 10.3389/fchem.2022.861288.

Design, synthesis and biological activity of N-phenylsubstituted-7H-pyrrolo[2,3-d]pyrimidin-4-amines as dual inhibitors of aurora kinase A and epidermal growth factor receptor kinase.

Kurup S, McAllister B, Liskova P, Mistry T, Fanizza A, Stanford D J Enzyme Inhib Med Chem. 2017; 33(1):74-84.

PMID: 29115879 PMC: 6009956. DOI: 10.1080/14756366.2017.1376666.

Discovery and preclinical evaluation of 7-benzyl-N-(substituted)-pyrrolo[3,2-d]pyrimidin-4-amines as single agents with microtubule targeting effects along with triple-acting angiokinase inhibition as antitumor agents.

Pavana R, Choudhary S, Bastian A, Ihnat M, Bai R, Hamel E Bioorg Med Chem. 2016; 25(2):545-556.

PMID: 27894589 PMC: 5191990. DOI: 10.1016/j.bmc.2016.11.026.

References

Tsou H, Overbeek-Klumpers E, Hallett W, Reich M, Floyd M, Johnson B . Optimization of 6,7-disubstituted-4-(arylamino)quinoline-3-carbonitriles as orally active, irreversible inhibitors of human epidermal growth factor receptor-2 kinase activity. J Med Chem. 2005; 48(4):1107-31. DOI: 10.1021/jm040159c. View

Kovalenko M, Gazit A, Bohmer A, Rorsman C, Ronnstrand L, Heldin C . Selective platelet-derived growth factor receptor kinase blockers reverse sis-transformation. Cancer Res. 1994; 54(23):6106-14. View

Levitzki A . Protein kinase inhibitors as a therapeutic modality. Acc Chem Res. 2003; 36(6):462-9. DOI: 10.1021/ar0201207. View

Sandler A, Herbst R . Combining targeted agents: blocking the epidermal growth factor and vascular endothelial growth factor pathways. Clin Cancer Res. 2006; 12(14 Pt 2):4421s-4425s. DOI: 10.1158/1078-0432.CCR-06-0796. View

Hubbard S . Protein tyrosine kinases: autoregulation and small-molecule inhibition. Curr Opin Struct Biol. 2002; 12(6):735-41. DOI: 10.1016/s0959-440x(02)00383-4. View

Gangjee A, Yang J, Ihnat M, Kamat S . Antiangiogenic and antitumor agents. Design, synthesis, and evaluation of novel 2-amino-4-(3-bromoanilino)-6-benzylsubstituted pyrrolo[2,3-d]pyrimidines as inhibitors of receptor tyrosine kinases. Bioorg Med Chem. 2003; 11(23):5155-70. DOI: 10.1016/j.bmc.2003.08.034. View

de Jonge M, Verweij J . Multiple targeted tyrosine kinase inhibition in the clinic: all for one or one for all?. Eur J Cancer. 2006; 42(10):1351-6. DOI: 10.1016/j.ejca.2006.02.013. View

Atkins M, Jones C, Kirkpatrick P . Sunitinib maleate. Nat Rev Drug Discov. 2006; 5(4):279-80. DOI: 10.1038/nrd2012. View

Hennequin L, Thomas A, Johnstone C, Stokes E, Ple P, LOHMANN J . Design and structure-activity relationship of a new class of potent VEGF receptor tyrosine kinase inhibitors. J Med Chem. 2000; 42(26):5369-89. DOI: 10.1021/jm990345w. View

10.

Manley P, Furet P, Bold G, Bruggen J, Mestan J, Meyer T . Anthranilic acid amides: a novel class of antiangiogenic VEGF receptor kinase inhibitors. J Med Chem. 2002; 45(26):5687-93. DOI: 10.1021/jm020899q. View

11.

Madhusudan S, Ganesan T . Tyrosine kinase inhibitors in cancer therapy. Clin Biochem. 2004; 37(7):618-35. DOI: 10.1016/j.clinbiochem.2004.05.006. View

12.

Bridges A, Zhou H, Cody D, Rewcastle G, McMichael A, Showalter H . Tyrosine kinase inhibitors. 8. An unusually steep structure-activity relationship for analogues of 4-(3-bromoanilino)-6,7-dimethoxyquinazoline (PD 153035), a potent inhibitor of the epidermal growth factor receptor. J Med Chem. 1996; 39(1):267-76. DOI: 10.1021/jm9503613. View

13.

Rak J, Yu J, Klement G, Kerbel R . Oncogenes and angiogenesis: signaling three-dimensional tumor growth. J Investig Dermatol Symp Proc. 2001; 5(1):24-33. DOI: 10.1046/j.1087-0024.2000.00012.x. View

14.

Wilhelm S, Carter C, Lynch M, Lowinger T, Dumas J, Smith R . Discovery and development of sorafenib: a multikinase inhibitor for treating cancer. Nat Rev Drug Discov. 2006; 5(10):835-44. DOI: 10.1038/nrd2130. View

15.

Arora A, Scholar E . Role of tyrosine kinase inhibitors in cancer therapy. J Pharmacol Exp Ther. 2005; 315(3):971-9. DOI: 10.1124/jpet.105.084145. View

16.

Wissner A, Overbeek E, Reich M, Floyd M, Johnson B, Mamuya N . Synthesis and structure-activity relationships of 6,7-disubstituted 4-anilinoquinoline-3-carbonitriles. The design of an orally active, irreversible inhibitor of the tyrosine kinase activity of the epidermal growth factor receptor (EGFR) and the.... J Med Chem. 2002; 46(1):49-63. DOI: 10.1021/jm020241c. View

17.

Sun , McMahon . Inhibition of tumor angiogenesis by synthetic receptor tyrosine kinase inhibitors. Drug Discov Today. 2000; 5(8):344-353. DOI: 10.1016/s1359-6446(00)01534-8. View

18.

Bold G, Altmann K, Frei J, Lang M, Manley P, Traxler P . New anilinophthalazines as potent and orally well absorbed inhibitors of the VEGF receptor tyrosine kinases useful as antagonists of tumor-driven angiogenesis. J Med Chem. 2000; 43(12):2310-23. DOI: 10.1021/jm9909443. View

19.

Wilson S, Barsoum M, Wilson B, Pappone P . Purine nucleotides modulate proliferation of brown fat preadipocytes. Cell Prolif. 1999; 32(2-3):131-40. PMC: 6726323. DOI: 10.1046/j.1365-2184.1999.32230131.x. View

20.

Folkman J . Angiogenesis: an organizing principle for drug discovery?. Nat Rev Drug Discov. 2007; 6(4):273-86. DOI: 10.1038/nrd2115. View