title: Identification and optimisation of a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors.
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.
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: Richard J
authors.initials: RJ
authors.lastname: Bull
authors.forename: David E
authors.initials: DE
authors.lastname: Clark
authors.forename: Peter H
authors.initials: PH
authors.lastname: Crackett
authors.forename: Hazel J
authors.initials: HJ
authors.lastname: Dyke
authors.forename: Matthew
authors.initials: M
authors.lastname: Gill
authors.forename: Neil V
authors.initials: NV
authors.lastname: Harris
authors.forename: Julia
authors.initials: J
authors.lastname: Gorski
authors.forename: Julia
authors.initials: J
authors.lastname: Lloyd
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lockey
authors.forename: Julia
authors.initials: J
authors.lastname: Mullett
authors.forename: Alan G
authors.initials: AG
authors.lastname: Roach
authors.forename: Fabien
authors.initials: F
authors.lastname: Roussel
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; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003198:Computer Simulation; D004353:Drug Evaluation, Preclinical; 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; D051379:Mice; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000188:drug therapy; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D011720:Pyrazoles