Identification and optimisation of a series of substituted 5-(1H-pyrazol-3-yl)-thiophene-2-hydroxamic acids as potent histone deacetylase (HDAC) inhibitors.
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.
Price
Steve
S
Argenta Discovery Ltd, 8/9 Spire Green Centre, Flex Meadow, Harlow, Essex CM19 5TR, UK. steve.price@argentadiscovery.com
Bordogna
Walter
W
Bull
Richard J
RJ
Clark
David E
DE
Crackett
Peter H
PH
Dyke
Hazel J
HJ
Gill
Matthew
M
Harris
Neil V
NV
Gorski
Julia
J
Lloyd
Julia
J
Lockey
Peter M
PM
Mullett
Julia
J
Roach
Alan G
AG
Roussel
Fabien
F
White
Anne B
AB
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
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007202:Indicators and Reagents; D011720:Pyrazoles