2. Academic Validation
  3. Identification and optimisation of a series of substituted 5-pyridin-2-yl-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors

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

  • Bioorg Med Chem Lett. 2007 Jan 15;17(2):363-9. doi: 10.1016/j.bmcl.2006.10.045.
Steve Price 1,  Walter Bordogna,  Ruth Braganza,  Richard J Bull,  Hazel J Dyke,  Sophie Gardan,  Matthew Gill,  Neil V Harris,  Robert A Heald,  Marco van den Heuvel,  Peter M Lockey,  Julia Lloyd,  Aranzazu G Molina,  Alan G Roach,  Fabien Roussel,  Jonathan M Sutton,  Anne B White
Affiliations

Affiliation

  • 1 Argenta Discovery Ltd, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK. steve.price@argentadiscovery.com
PMID: 17107790 DOI: 10.1016/j.bmcl.2006.10.045
Abstract

Further investigation of a series of thienyl-based hydroxamic acids that included ADS100380 and ADS102550 led to the identification of the 5-pyridin-2-yl-thiophene-2-hydroxamic acid 3c, which possessed modest HDAC inhibitory activity. Substitution at the 5- and 6-positions of the pyridyl ring of compound 3c provided compounds 5a-g, 7a, b, 9, and 13a. Compound 5b demonstrated improved potency, in vitro DMPK profile, and rat oral bioavailability, compared to ADS102550. Functionalisation of the pendent phenyl group of compounds 5b, 5e and 13a provided analogues that possessed excellent enzyme inhibition and anti-proliferative activity.

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