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Bioorg Med Chem Lett. 2017 May 15;27(10):2185-2191. doi: 10.1016/j.bmcl.2017.03.073. Epub 2017 Mar 29.

Novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety for anaplastic lymphoma kinase (ALK) inhibitor.

Author information

1
Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
2
Department of Chemistry, Sogang University, Seoul 04107, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
3
Center for Convergent Research of Emerging Virus Infection, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
4
Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea.
5
Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: pkim@krict.re.kr.
6
Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 34113, Republic of Korea; Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 34114, Republic of Korea. Electronic address: jyhwang@krict.re.kr.

Abstract

In this study, a series of novel 2,4-diaminopyrimidines bearing fused tricyclic ring moiety was described for ALK inhibitor. The pyrazole, imidazole, 1,2,4-triazole, piperazine and phenanthridine moieties were employed at the 2-position of pyrimidine. Among the compounds synthesized, 28, 29, 36, and 42 showed promising anti-ALK activities in enzymatic- and cell-based assays. In vivo H3122 xenograft model study showed that compound 29 effectively suppressed ALK-driven tumor growth, similar to the extent of ceritinib, suggesting that it could be used for a novel ALK inhibitor development.

KEYWORDS:

2,4-Diaminopyrimidine; Anaplastic lymphoma kinase; Cancer; Fused tricyclic moiety

PMID:
28385505
DOI:
10.1016/j.bmcl.2017.03.073
[Indexed for MEDLINE]

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