title: Novel second generation analogs of eribulin. Part I: Compounds containing a lipophilic C32 side chain overcome P-glycoprotein susceptibility.
abstract: Eribulin mesylate (Halaven™), a totally synthetic analog of the marine polyether macrolide halichondrin B, has recently been approved in the United States as a treatment for breast cancer. It is also currently under regulatory review in Japan and the European Union. Our continuing medicinal chemistry efforts on this scaffold have focused on oral bioavailability, brain penetration and efficacy against multidrug resistant (MDR) tumors by lowering the susceptibility of these compounds to P-glycoprotein (P-gp)-mediated drug efflux. Replacement of the 1,2-amino alcohol C32 side chain of eribulin with fragments neutral at physiologic pH led to the identification of analogs with significantly lower P-gp susceptibility. The analogs maintained low- to sub-nM potency in vitro against both sensitive and MDR cell lines. Within this series, increasing lipophilicity generally led to decreased P-gp susceptibility. In addition to potency in cell culture, these compounds showed in vivo activity in mouse xenograft models.
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: Hong
authors.initials: H
authors.lastname: Du
authors.forename: Yongbo
authors.initials: Y
authors.lastname: Hu
authors.forename: Yimin
authors.initials: Y
authors.lastname: Jiang
authors.forename: Bryan M
authors.initials: BM
authors.lastname: Lewis
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: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D001682:Biological Availability; D045744:Cell Line, Tumor; D005663:Furans / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007659:Ketones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology; D051379:Mice; D013329:Structure-Activity Relationship; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000970:Antineoplastic Agents; D005663:Furans; D007659:Ketones; C490954:eribulin; D000095662:Polyether Polyketides