title: Structure-based design of novel, urea-containing FKBP12 inhibitors.
abstract: The structure-based design and subsequent chemical synthesis of novel, urea-containing FKBP12 inhibitors are described. These compounds are shown to disrupt the cis-trans peptidylprolyl isomerase activity of FKBP12 with inhibition constants (Ki,app) approaching 0.10 microM. Analyses of several X-ray crystal structures of FKBP12-urea complexes demonstrate that the urea-containing inhibitors associate with FKBP12 in a manner that is similar to, but significantly different from, that observed for the natural product FK506.
authors.affiliation: Agouron Pharmaceuticals, Inc., San Diego, California 92121, USA.
authors.forename: P S
authors.initials: PS
authors.lastname: Dragovich
authors.forename: J E
authors.initials: JE
authors.lastname: Barker
authors.forename: J
authors.initials: J
authors.lastname: French
authors.forename: M
authors.initials: M
authors.lastname: Imbacuan
authors.forename: V J
authors.initials: VJ
authors.lastname: Kalish
authors.forename: C R
authors.initials: CR
authors.lastname: Kissinger
authors.forename: D R
authors.initials: DR
authors.lastname: Knighton
authors.forename: C T
authors.initials: CT
authors.lastname: Lewis
authors.forename: E W
authors.initials: EW
authors.lastname: Moomaw
authors.forename: H E
authors.initials: HE
authors.lastname: Parge
authors.forename: L A
authors.initials: LA
authors.lastname: Pelletier
authors.forename: T J
authors.initials: TJ
authors.lastname: Prins
authors.forename: R E
authors.initials: RE
authors.lastname: Showalter
authors.forename: J H
authors.initials: JH
authors.lastname: Tatlock
authors.forename: K D
authors.initials: KD
authors.lastname: Tucker
authors.forename: J E
authors.initials: JE
authors.lastname: Villafranca
mesh_terms: D000591:Amino Acid Isomerases / Q000037:antagonists & inhibitors; D000595:Amino Acid Sequence; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D018360:Crystallography, X-Ray; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D015195:Drug Design; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D019696:Peptidylprolyl Isomerase; D013329:Structure-Activity Relationship; D016559:Tacrolimus / Q000737:chemistry; D022021:Tacrolimus Binding Proteins; D014508:Urea / Q000032:analysis*
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006360:Heat-Shock Proteins; D014508:Urea; D000591:Amino Acid Isomerases; D022021:Tacrolimus Binding Proteins; D019696:Peptidylprolyl Isomerase; D016559:Tacrolimus