title: Identification and optimisation of a series of substituted 5-pyridin-2-yl-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors.
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.
authors.affiliation: Argenta Discovery Ltd, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK. steve.price@argentadiscovery.com
authors.forename: Steve
authors.initials: S
authors.lastname: Price
authors.forename: Walter
authors.initials: W
authors.lastname: Bordogna
authors.forename: Ruth
authors.initials: R
authors.lastname: Braganza
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Bull
authors.forename: Hazel J
authors.initials: HJ
authors.lastname: Dyke
authors.forename: Sophie
authors.initials: S
authors.lastname: Gardan
authors.forename: Matthew
authors.initials: M
authors.lastname: Gill
authors.forename: Neil V
authors.initials: NV
authors.lastname: Harris
authors.forename: Robert A
authors.initials: RA
authors.lastname: Heald
authors.forename: Marco
authors.initials: M
authors.lastname: van den Heuvel
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lockey
authors.forename: Julia
authors.initials: J
authors.lastname: Lloyd
authors.forename: Aranzazu G
authors.initials: AG
authors.lastname: Molina
authors.forename: Alan G
authors.initials: AG
authors.lastname: Roach
authors.forename: Fabien
authors.initials: F
authors.lastname: Roussel
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Sutton
authors.forename: Anne B
authors.initials: AB
authors.lastname: White
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D001682:Biological Availability; D018938:Caco-2 Cells; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D051544:Cytochrome P-450 CYP3A; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000138:chemical synthesis* / Q000494:pharmacology*; D007202:Indicators and Reagents; D007275:Injections, Intravenous; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D051381:Rats; D013329:Structure-Activity Relationship; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D013876:Thiophenes; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human