Author/Authors :
Steve Price، نويسنده , , Walter Bordogna، نويسنده , , Ruth Braganza، نويسنده , , Richard J. Bull، نويسنده , , Hazel J. Dyke، نويسنده , , Sophie Gardan، نويسنده , , Matthew Gill، نويسنده , , Neil V. Harris، نويسنده , , Robert A. Heald، نويسنده , , Marco van den Heuvel، نويسنده , , Peter M. Lockey، نويسنده , , Julia Lloyd، نويسنده , , Aranzazu G. Molina، نويسنده , , Alan G. Roach، نويسنده , , Fabien Roussel، نويسنده , , Jonathan M. Sutton، نويسنده , , Anne B. White، نويسنده ,
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.
