New antimitotic agents with activity in multi-drug-resistant cell lines and in vivo efficacy in murine tumor models

  • J Med Chem. 2001 Dec 6;44(25):4416-30. doi: 10.1021/jm010231w.
B G Szczepankiewicz  1 ,  G Liu ,  H S Jae ,  A S Tasker ,  I W Gunawardana ,  T W von Geldern ,  S L Gwaltney 2nd ,  J R Wu-Wong ,  L Gehrke ,  W J Chiou ,  R B Credo ,  J D Alder ,  M A Nukkala ,  N A Zielinski ,  K Jarvis ,  K W Mollison ,  D J Frost ,  J L Bauch ,  Y H Hui ,  A K Claiborne ,  Q Li ,  S H Rosenberg
Affiliations
  • 1. Pharmaceutical Products Division, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, Illinois 60064, USA. [email protected]
PMID: 11728187 DOI: 10.1021/jm010231w
Abstract

During a screen for compounds that could inhibit cell proliferation, a series of new tubulin-binding compounds was identified with the discovery of oxadiazoline 1 (A-105972). This compound showed good cytotoxic activity against non-multi-drug-resistant and multi-drug-resistant Cancer cell lines, but its utility in vivo was limited by a short half-life. Medicinal chemistry efforts led to the discovery of indolyloxazoline 22g (A-259745), which maintained all of the in vitro activity seen with oxadiazoline 1, but also demonstrated a better pharmacokinetic profile, and dose-dependent in vivo activity. Over a 28 day study, indolyloxazoline 22g increased the life span of tumor-implanted mice by up to a factor of 3 upon oral dosing. This compound, and Others of its structural class, may prove to be useful in the development of new chemotherapeutic agents to treat human cancers.

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