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  3. Novel second generation analogs of eribulin. Part III: Blood-brain barrier permeability and in vivo activity in a brain tumor model

Novel second generation analogs of eribulin. Part III: Blood-brain barrier permeability and in vivo activity in a brain tumor model

  • Bioorg Med Chem Lett. 2011 Mar 15;21(6):1639-43. doi: 10.1016/j.bmcl.2011.01.096.
Sridhar Narayan 1,  Eric M Carlson,  Hongsheng Cheng,  Krista Condon,  Hong Du,  Sean Eckley,  Yongbo Hu,  Yimin Jiang,  Vipul Kumar,  Bryan M Lewis,  Philip Saxton,  Edgar Schuck,  Boris M Seletsky,  Karen Tendyke,  Huiming Zhang,  Wanjun Zheng,  Bruce A Littlefield,  Murray J Towle,  Melvin J Yu
Affiliations

Affiliation

  • 1 Eisai Product Creation Systems, Eisai Inc., Andover, MA 01810, USA. Sridhar_Narayan@eisai.com
PMID: 21324687 DOI: 10.1016/j.bmcl.2011.01.096
Abstract

Novel second generation analogs of eribulin mesylate, a tubulin agent recently approved for the treatment of breast Cancer, are reported. Our recent efforts have focused on expanding the target indications for this class of compounds to Other tumor types. Herein, we describe the design, synthesis and evaluation of eribulin analogs active against brain tumor cell lines in vitro and corresponding brain tumor models in mice. Attenuation of basicity of the amino group(s) in the C32 side-chain region led to compounds with lower susceptibility to P-gp mediated drug efflux, allowing these compounds to permeate through the blood-brain barrier. In preclinical in vivo studies, these compounds showed significantly higher levels in the brain and cerebrospinal fluid as compared to eribulin. In addition, analogs within this series showed antitumor activity in an orthotopic murine model of human glioblastoma.

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