The discovery of 6-amino nicotinamides as potent and selective histone deacetylase inhibitors

• Published in: Bioorganic & medicinal chemistry letters Vol. 17; no. 19; pp. 5300 - 5309
• Main Authors: Hamblett, Christopher L., Methot, Joey L., Mampreian, Dawn M., Sloman, David L., Stanton, Matthew G., Kral, Astrid M., Fleming, Judith C., Cruz, Jonathan C., Chenard, Melissa, Ozerova, Nicole, Hitz, Anna M., Wang, Hongmei, Deshmukh, Sujal V., Nazef, Naim, Harsch, Andreas, Hughes, Bethany, Dahlberg, William K., Szewczak, Alex A., Middleton, Richard E., Mosley, Ralph T., Secrist, J. Paul, Miller, Thomas A.
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 01.10.2007; Elsevier
• Subjects: 6-Aminonicotinamide - analogs & derivatives; 6-Aminonicotinamide - chemical synthesis; 6-Aminonicotinamide - pharmacology; Animals; Antineoplastic agents; Area Under Curve; Benzamides; Benzamides - chemistry; Biological and medical sciences; Biological Availability; Cell Line, Tumor; Cell Membrane Permeability - drug effects; Dogs; Drug Design; Drug Screening Assays, Antitumor; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacokinetics; Enzyme Inhibitors - pharmacology; Epigenetics; General aspects; Half-Life; Histone acetylation; Histone Deacetylase Inhibitors; Histone deacetylases; Humans; Isoenzymes - antagonists & inhibitors; Medical sciences; Miscellaneous; Models, Molecular; Neoplasm Transplantation; Nicotinamides; Pharmacology. Drug treatments; Protein Binding; Rats; Structure-Activity Relationship; Substrate Specificity; Epigenetics; Histone acetylation; Nicotinamides; Benzamides; Histone deacetylases; Antineoplastic agent; Intravenous administration; Rat; Nitrogen heterocycle; Cytotoxicity; Selectivity; Organic carbamate; Pyridine derivatives; Structure activity relation; Molecular model; Binding mode; Chemical synthesis; Dog; Tumor cell; Human; Fissipedia; Rodentia; Enzyme inhibitor; Inhibitor enzyme complex; Vertebrata; Chemotherapy; Animal; Carboxamide; Piperazine derivatives; Solid tumor; Modeling; Colon cancer; Colon; Anilide; Carnivora; Enzyme; Oral administration; Malignant tumor; In vitro; In vivo; Histone deacetylase inhibitor; Mammalia; Treatment; Cell line; Mouse; Hydrolases; Pharmacokinetics; Cancer; Aromatic amine
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2007.08.023

This communication highlights the development of a nicotinamide series of histone deacetylase inhibitors within the benzamide structural class. Extensive exploration around the nicotinamide core led to the discovery of a class I selective HDAC inhibitor that possesses excellent intrinsic and cell-based potency, acceptable ancillary pharmacology, favorable pharmacokinetics, sustained pharmacodynamics in vitro, and achieves in vivo efficacy in an HCT116 xenograft model.