title: Design of novel histone deacetylase inhibitors.
abstract: Histone deacetylase (HDAC) inhibitors that target Class I and Class II HDACs are of synthetic and therapeutic interest and ongoing clinical studies indicate that they show great promise for the treatment of cancer. Moreover, Zolinza (vorinostat) was recently approved by the FDA for the treatment of the cutaneous manifestations of cutaneous T-cell lymphoma [Nat. Rev. Drug Disc. 2007, 6, 21]. As part of a broader effort to more fully explore the structure-activity relationships (SAR) of HDAC inhibitors, we sought to identify novel HDAC inhibitor structures through iterative design by utilizing low affinity ligands as synthetic starting points for SAR development. Novel and potent HDAC inhibitors have been identified using this approach and herein we report the optimization of the recognition elements of a novel series of malonyl-derived HDAC inhibitors.
authors.affiliation: Department of Drug Design & Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. Phieng_silphaivanh@merck.com
authors.forename: Phieng
authors.initials: P
authors.lastname: Siliphaivanh
authors.forename: Paul
authors.initials: P
authors.lastname: Harrington
authors.forename: David J
authors.initials: DJ
authors.lastname: Witter
authors.forename: Karin
authors.initials: K
authors.lastname: Otte
authors.forename: Paul
authors.initials: P
authors.lastname: Tempest
authors.forename: Sam
authors.initials: S
authors.lastname: Kattar
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Kral
authors.forename: Judith C
authors.initials: JC
authors.lastname: Fleming
authors.forename: Sujal V
authors.initials: SV
authors.lastname: Deshmukh
authors.forename: Andreas
authors.initials: A
authors.lastname: Harsch
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Secrist
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015195:Drug Design; D056572:Histone Deacetylase Inhibitors; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D056572:Histone Deacetylase Inhibitors