ABSTRACT
MAPKAPK5 has been proposed to play a role in regulation of matrix metalloprotease expression and so to be a potential target for intervention in rheumatoid arthritis. We present here the identification of a series of compounds against this target which are effective in both biochemical and cell assays. The expansion of the series is described, along with early SAR and pharmacokinetics for some representative compounds.
Subject(s)
Antirheumatic Agents/chemical synthesis , Imidazoles/chemical synthesis , Intracellular Signaling Peptides and Proteins/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyrazoles/chemical synthesis , Animals , Antirheumatic Agents/pharmacokinetics , Antirheumatic Agents/pharmacology , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/enzymology , Binding Sites , High-Throughput Screening Assays , Humans , Hydrogen Bonding , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Intracellular Signaling Peptides and Proteins/metabolism , Models, Molecular , Protein Binding , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/metabolism , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Small Molecule Libraries , Structure-Activity RelationshipABSTRACT
This article reviews the literature from January 2004 to January 2006 relating to the use of parallel chemistry compound libraries in drug discovery. Examples of libraries that have yielded active compounds across a range of biological targets are presented, together with synthetic details where relevant. The background of the biological target, and any structure-activity relationship that can be discerned from members of a library series, are also commented upon. A brief discussion of new technological developments in library design and synthesis, and likely future directions for parallel chemistry in the context of drug discovery, is also presented.
