Synthesis and evaluation of novel 2,4-diaminopyrimidines bearing bicyclic aminobenzazepines for anaplastic lymphoma kinase (ALK) inhibitor

Bioorg Med Chem Lett. 2015 Sep 15;25(18):3992-8. doi: 10.1016/j.bmcl.2015.07.004.

Ga Ae Kang ¹, Minji Lee ², Dawn Song ³, Heung Kyoung Lee ¹, Sunjoo Ahn ⁴, Chi Hoon Park ⁴, Chong Ock Lee ¹, Chang Soo Yun ⁴, Heejung Jung ⁴, Pilho Kim ⁴, Jae Du Ha ¹, Sung Yun Cho ⁴, Hyoung Rae Kim ⁵, Jong Yeon Hwang ⁶

Affiliations

1 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea.
2 Department of Chemistry, Korea University, Seoul 136-701, Republic of Korea.
3 College of Pharmacy, Chungbuk National University, Cheongju, Chungbuk 362-763, Republic of Korea.
4 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea.
5 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea. Electronic address: [email protected].
6 Bio & Drug Discovery Division, Korea Research Institute of Chemical Technology, Daejeon 305-600, Republic of Korea; Department of Medicinal Chemistry and Pharmacology, University of Science & Technology, Daejeon 305-550, Republic of Korea. Electronic address: [email protected].

PMID: 26235945 DOI: 10.1016/j.bmcl.2015.07.004

Abstract

A series of novel 2,4-diaminopyrimidine compounds bearing bicyclic aminobenzazepine were synthesized and evaluated for their anti-ALK activities. The activities of these compounds were confirmed in both enzyme- and cell-based ALK assays. Amongst compounds synthesized, KRCA-0445 showed very promising results in pharmacokinetic study and in vivo efficacy study with H3122 xenograft mouse model.

Keywords

2,4-Diaminopyrimidine; ALK; Cancer.

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