title: Exploring the pharmacokinetic properties of phosphorus-containing selective HDAC 1 and 2 inhibitors (SHI-1:2).
abstract: We report the preparation and structure-activity relationships of phosphorus-containing histone deacetylase inhibitors. A strong trend between decreasing phosphorus functional group size and superior mouse pharmacokinetic properties was identified. In addition, optimized candidates showed tumor growth inhibition in xenograft studies.
authors.affiliation: Department of Drug Design and Optimization, Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA. richard_heidebrecht@merck.com
authors.forename: Richard W
authors.initials: RW
authors.lastname: Heidebrecht
authors.forename: Melissa
authors.initials: M
authors.lastname: Chenard
authors.forename: Joshua
authors.initials: J
authors.lastname: Close
authors.forename: William K
authors.initials: WK
authors.lastname: Dahlberg
authors.forename: Judith
authors.initials: J
authors.lastname: Fleming
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Grimm
authors.forename: Julie E
authors.initials: JE
authors.lastname: Hamill
authors.forename: Andreas
authors.initials: A
authors.lastname: Harsch
authors.forename: Brian B
authors.initials: BB
authors.lastname: Haines
authors.forename: Bethany
authors.initials: B
authors.lastname: Hughes
authors.forename: Astrid M
authors.initials: AM
authors.lastname: Kral
authors.forename: Richard E
authors.initials: RE
authors.lastname: Middleton
authors.forename: Chandrasekhar
authors.initials: C
authors.lastname: Mushti
authors.forename: Nicole
authors.initials: N
authors.lastname: Ozerova
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Szewczak
authors.forename: Hongmei
authors.initials: H
authors.lastname: Wang
authors.forename: Kevin
authors.initials: K
authors.lastname: Wilson
authors.forename: David J
authors.initials: DJ
authors.lastname: Witter
authors.forename: J Paul
authors.initials: JP
authors.lastname: Secrist
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Miller
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D063065:Organophosphonates / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics*; D012097:Repressor Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D063065:Organophosphonates; D012097:Repressor Proteins; C484389:Hdac1 protein, mouse; C533424:Hdac2 protein, mouse; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D006655:Histone Deacetylases