ABSTRACT
Advances in the field of drug discovery have brought an explosion in the quantity of data available to medicinal chemists and other project team members. New strategies and systems are needed to help these scientists to efficiently gather, organize, analyze, annotate, and share data about potential new drug molecules of interest to their project teams. Herein we describe a suite of integrated services and end-user applications that facilitate these activities throughout the medicinal chemistry design cycle. The Automated Data Presentation (ADP) and Virtual Compound Profiler (VCP) processes automate the gathering, organization, and storage of real and virtual molecules, respectively, and associated data. The Project-Focused Activity and Knowledge Tracker (PFAKT) provides a unified data analysis and collaboration environment, enhancing decision-making, improving team communication, and increasing efficiency.
Subject(s)
Chemistry, Pharmaceutical/methods , Cooperative Behavior , Group Processes , Statistics as Topic/methods , Workflow , Chemistry, Pharmaceutical/organization & administration , Communication , Drug Design , Industry , Information Storage and Retrieval , Knowledge , User-Computer InterfaceABSTRACT
The synthesis and structure-activity relationships (SAR) of a series of benzothiophene piperazine and piperidine urea FAAH inhibitors is described. These compounds inhibit FAAH by covalently modifying the enzyme's active site serine nucleophile. Activity-based protein profiling (ABPP) revealed that these urea inhibitors were completely selective for FAAH relative to other mammalian serine hydrolases. Several compounds showed in vivo activity in a rat complete Freund's adjuvant (CFA) model of inflammatory pain.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Piperazines/chemistry , Piperidines/chemistry , Thiophenes/chemistry , Urea/analogs & derivatives , Amidohydrolases/metabolism , Animals , Computer Simulation , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Humans , Models, Chemical , Piperazines/chemical synthesis , Piperazines/pharmacology , Piperidines/chemical synthesis , Piperidines/pharmacology , Rats , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacology , Urea/chemical synthesis , Urea/pharmacologyABSTRACT
A series of 3-imino-2-indolones are the first published, high-affinity antagonists of the galanin GAL3 receptor. One example, 1,3-dihydro-1-phenyl-3-[[3-(trifluoromethyl)phenyl]imino]-2H-indol-2-one (9), was shown to have high affinity for the human GAL3 receptor (Ki=17 nM) and to be highly selective for GAL3 over a broad panel of targets, including GAL1 and GAL2. Compound 9 was also shown to be an antagonist in a human GAL3 receptor functional assay (Kb=29 nM).
Subject(s)
Imines/chemical synthesis , Indoles/chemical synthesis , Receptor, Galanin, Type 3/antagonists & inhibitors , Animals , Binding, Competitive , Brain/metabolism , COS Cells , Chlorocebus aethiops , Cyclic AMP/biosynthesis , Humans , Imines/pharmacokinetics , Imines/pharmacology , Indoles/pharmacokinetics , Indoles/pharmacology , Ligands , Radioligand Assay , Rats , Receptor, Galanin, Type 1/drug effects , Receptor, Galanin, Type 2/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
Several new, potent dopamine subtype 2 (DA D(2)) active compounds with serotonin subtype 2A (5-HT(2A)) pharmacology are presented. 8-Substituted 3,4-dihydroquinolinones, tetrahydroquinolines, and N-acyl tetrahydroquinolines were evaluated in primary assays. Subtle changes on this novel scaffold translated to large changes in potency and selectivity in vitro. These compounds show promise as novel atypical antipsychotics for the treatment of schizophrenia.
