Identification and optimisation of a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors

  • Bioorg Med Chem Lett. 2007 Jan 15;17(2):370-5. doi: 10.1016/j.bmcl.2006.10.048.
Steve Price  1 ,  Walter Bordogna ,  Richard J Bull ,  David E Clark ,  Peter H Crackett ,  Hazel J Dyke ,  Matthew Gill ,  Neil V Harris ,  Julia Gorski ,  Julia Lloyd ,  Peter M Lockey ,  Julia Mullett ,  Alan G Roach ,  Fabien Roussel ,  Anne B White
Affiliations
  • 1. Argenta Discovery Ltd, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK. [email protected]
PMID: 17095213 DOI: 10.1016/j.bmcl.2006.10.048
Abstract

Optimisation of ADS100380, a sub-micromolar HDAC Inhibitor identified using a virtual screening approach, led to a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids (6a-i), that possessed significant HDAC inhibitory activity. Subsequent functionalisation of the pendent phenyl group of compounds 6f and 6g provided analogues 6j-w with further enhanced enzyme and anti-proliferative activity. Compound 6j demonstrated efficacy in a mouse xenograft experiment.