ABSTRACT
A series of 2-arylindole-3-acetamide farnesyl protein transferase inhibitors has been identified. The compounds inhibit the enzyme in a farnesyl pyrophosphate-competitive manner and are selective for farnesyl protein transferase over the related enzyme geranylgeranyltransferase-I. A representative member of this series of inhibitors demonstrates equal effectiveness against HDJ-2 and K-Ras farnesylation in a cell-based assay when geranylgeranylation is suppressed.
Subject(s)
Alkyl and Aryl Transferases/antagonists & inhibitors , Indoleacetic Acids/metabolism , Indoleacetic Acids/pharmacology , Protein Prenylation/drug effects , ras Proteins/metabolism , Alkyl and Aryl Transferases/metabolism , Carrier Proteins/metabolism , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , HSP40 Heat-Shock Proteins , Heat-Shock Proteins/metabolism , Humans , Indoleacetic Acids/chemical synthesis , Protein Prenylation/physiology , Structure-Activity Relationship , Tumor Cells, CulturedABSTRACT
Structure-activity studies on the oxytocin antagonist 1 (L-371,257; Ki = 9.3 nM) have led to the identification of a related series of compounds containing an ortho-trifluoroethoxyphenylacetyl core which are orally bioavailable and have significantly improved potency in vitro and in vivo, e.g., compound 8 (L-374,943; Ki = 1.4 nM).
Subject(s)
Oxazines/chemical synthesis , Oxazines/pharmacokinetics , Oxytocin/antagonists & inhibitors , Piperidines/chemical synthesis , Piperidines/pharmacokinetics , Animals , Benzoxazines , Cell Line , Humans , Inhibitory Concentration 50 , Kinetics , Rats , Structure-Activity RelationshipABSTRACT
Structure-activity studies on the oxytocin antagonist 1 (L-371,257) have identified a new series of high affinity, receptor-selective OT antagonists in which the N-acetyl-4-piperidinyl ether terminus in 1 has been replaced with a 1-(aryl)ethoxy group.
