title: Evaluation of amino acid-based linkers in potent macrocyclic inhibitors of farnesyl-protein transferase.
abstract: A series of amino acid-based linkers was used to investigate the effects of various substituents upon the potency, pharmacokinetic properties, and conformation of macrocyclic farnesyl-protein transferase inhibitors (FTIs). As a result of the studies described herein, highly potent FTIs with improved pharmacokinetic profiles have been identified.
authors.affiliation: Department of Medicinal Chemistry, Merck Research Laboratories, PA 19486, West Point, USA. douglas_beshore@merck.com
authors.forename: D C
authors.initials: DC
authors.lastname: Beshore
authors.forename: I M
authors.initials: IM
authors.lastname: Bell
authors.forename: C J
authors.initials: CJ
authors.lastname: Dinsmore
authors.forename: C F
authors.initials: CF
authors.lastname: Homnick
authors.forename: J C
authors.initials: JC
authors.lastname: Culberson
authors.forename: R G
authors.initials: RG
authors.lastname: Robinson
authors.forename: C
authors.initials: C
authors.lastname: Fernandes
authors.forename: E S
authors.initials: ES
authors.lastname: Walsh
authors.forename: M T
authors.initials: MT
authors.lastname: Abrams
authors.forename: H G
authors.initials: HG
authors.lastname: Bhimnathwala
authors.forename: J P
authors.initials: JP
authors.lastname: Davide
authors.forename: M S
authors.initials: MS
authors.lastname: Ellis-Hutchings
authors.forename: H A
authors.initials: HA
authors.lastname: Huber
authors.forename: K S
authors.initials: KS
authors.lastname: Koblan
authors.forename: C A
authors.initials: CA
authors.lastname: Buser
authors.forename: N E
authors.initials: NE
authors.lastname: Kohl
authors.forename: R B
authors.initials: RB
authors.lastname: Lobell
authors.forename: I W
authors.initials: IW
authors.lastname: Chen
authors.forename: D A
authors.initials: DA
authors.lastname: McLoughlin
authors.forename: T V
authors.initials: TV
authors.lastname: Olah
authors.forename: S L
authors.initials: SL
authors.lastname: Graham
authors.forename: G D
authors.initials: GD
authors.lastname: Hartman
authors.forename: T M
authors.initials: TM
authors.lastname: Williams
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000187:drug effects*; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D002478:Cells, Cultured; D004285:Dogs; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics*; D006207:Half-Life; D020128:Inhibitory Concentration 50; D008657:Metabolic Clearance Rate / Q000502:physiology; D008968:Molecular Conformation; D011485:Protein Binding / Q000187:drug effects; D051381:Rats
chemical_list: D000596:Amino Acids; D004791:Enzyme Inhibitors; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C064911:p21(ras) farnesyl-protein transferase