title: Structure-activity relationships of substituted 1-pyridyl-2-phenyl-1,2-ethanediones: potent, selective carboxylesterase inhibitors.
abstract: Inhibition of intestinal carboxylesterases may allow modification of the pharmacokinetics/pharmacodynamic profile of existing drugs by altering half-life or toxicity. Since previously identified diarylethane-1,2-dione inhibitors are decidedly hydrophobic, a modified dione scaffold was designed and elaborated into a >300 member library, which was subsequently screened to establish the SAR for esterase inhibition. This allowed the identification of single digit nanomolar hiCE inhibitors that showed improvement in selectivity and measured solubility.
authors.affiliation: Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
authors.forename: Brandon M
authors.initials: BM
authors.lastname: Young
authors.forename: Janice L
authors.initials: JL
authors.lastname: Hyatt
authors.forename: David C
authors.initials: DC
authors.lastname: Bouck
authors.forename: Taosheng
authors.initials: T
authors.lastname: Chen
authors.forename: Parimala
authors.initials: P
authors.lastname: Hanumesh
authors.forename: Jeanine
authors.initials: J
authors.lastname: Price
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Boyd
authors.forename: Philip M
authors.initials: PM
authors.lastname: Potter
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Webb
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D002091:Butyrylcholinesterase / Q000737:chemistry; D043182:Carboxylesterase / Q000037:antagonists & inhibitors*; D002800:Cholinesterase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D006037:Glyoxal / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D011725:Pyridines; D054852:Small Molecule Libraries; D006037:Glyoxal; D043182:Carboxylesterase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase