title: Novel second generation analogs of eribulin. Part III: Blood-brain barrier permeability and in vivo activity in a brain tumor model.
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.
authors.affiliation: Eisai Product Creation Systems, Eisai Inc., Andover, MA 01810, USA. Sridhar_Narayan@eisai.com
authors.forename: Sridhar
authors.initials: S
authors.lastname: Narayan
authors.forename: Eric M
authors.initials: EM
authors.lastname: Carlson
authors.forename: Hongsheng
authors.initials: H
authors.lastname: Cheng
authors.forename: Krista
authors.initials: K
authors.lastname: Condon
authors.forename: Hong
authors.initials: H
authors.lastname: Du
authors.forename: Sean
authors.initials: S
authors.lastname: Eckley
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Hu
authors.forename: Yimin
authors.initials: Y
authors.lastname: Jiang
authors.forename: Vipul
authors.initials: V
authors.lastname: Kumar
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Lewis
authors.forename: Philip
authors.initials: P
authors.lastname: Saxton
authors.forename: Edgar
authors.initials: E
authors.lastname: Schuck
authors.forename: Boris M
authors.initials: BM
authors.lastname: Seletsky
authors.forename: Karen
authors.initials: K
authors.lastname: Tendyke
authors.forename: Huiming
authors.initials: H
authors.lastname: Zhang
authors.forename: Wanjun
authors.initials: W
authors.lastname: Zheng
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Littlefield
authors.forename: Murray J
authors.initials: MJ
authors.lastname: Towle
authors.forename: Melvin J
authors.initials: MJ
authors.lastname: Yu
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D001812:Blood-Brain Barrier; D001932:Brain Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005663:Furans / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D051379:Mice; D008807:Mice, Inbred BALB C; D000095662:Polyether Polyketides
chemical_list: D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; C490954:eribulin; D000095662:Polyether Polyketides