ABSTRACT
This paper details exploration of a class of triazole-based cathepsin S inhibitors originally reported by Ellman and co-workers. SAR studies involving modifications across the whole inhibitor provide a perspective on the strengths and weaknesses of this class of inhibitors. In addition, we put the unique characteristics of this class of compounds into perspective with other classes of cathepsin S inhibitors.
Subject(s)
Amides/chemistry , Cathepsins/antagonists & inhibitors , Protease Inhibitors/chemistry , Thiophenes/chemistry , Triazoles/chemistry , Cathepsins/metabolism , Half-Life , Humans , Microsomes, Liver/metabolism , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacokinetics , Protein Binding , Structure-Activity Relationship , Thiophenes/chemical synthesis , Thiophenes/pharmacokinetics , Triazoles/chemical synthesis , Triazoles/pharmacokineticsABSTRACT
A high throughput screening campaign identified aryl 1,4-diazepane compounds as potent and selective cannabinoid receptor 2 agonists as compared to cannabinoid receptor 1. This class of compounds suffered from poor drug-like parameters as well as low microsomal stability and poor solubility. Structure-activity relationships are described with a focus on improving the drug-like parameters resulting in compounds with improved solubility and permeability.
Subject(s)
Azepines/chemistry , Receptor, Cannabinoid, CB2/agonists , Azepines/pharmacology , Caco-2 Cells , Cell Membrane Permeability , High-Throughput Screening Assays , Humans , Microsomes, Liver/metabolism , Receptor, Cannabinoid, CB1/agonists , Receptor, Cannabinoid, CB1/metabolism , Receptor, Cannabinoid, CB2/metabolism , Solubility , Structure-Activity RelationshipABSTRACT
A high-throughput screening campaign has identified 1,4-diazepane compounds which are potent Cannabinoid receptor 2 agonists with excellent selectivity against the Cannabinoid receptor 1. This class of compounds suffered from low metabolic stability. Following various strategies, compounds with a good stability in liver microsomes and rat PK profile have been identified.
Subject(s)
Azepines/pharmacology , Receptor, Cannabinoid, CB2/agonists , Animals , Azepines/chemistry , Microsomes, Liver/metabolism , Rats , Rats, WistarABSTRACT
Identification and optimization of two classes of CB2 selective agonists are described. A representative from each class is profiled in a murine model of inflammation and each shows similar efficacy to prednisolone upon oral dosing.
Subject(s)
Morpholines/chemical synthesis , Receptor, Cannabinoid, CB2/agonists , Analgesics/chemical synthesis , Analgesics/pharmacology , Animals , Anti-Inflammatory Agents/pharmacology , Cell Line , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inflammation , Mice , Models, Chemical , Molecular Structure , Morpholines/pharmacology , Receptor, Cannabinoid, CB2/chemistry , StereoisomerismABSTRACT
A high-throughput screening campaign resulted in the discovery of a highly potent dual cannabinoid receptor 1 (CB1) and 2 (CB2) agonist. Following a thorough SAR exploration, a series of selective CB2 full agonists were identified.
Subject(s)
Receptor, Cannabinoid, CB2/agonists , Molecular Structure , Receptor, Cannabinoid, CB1/agonists , Structure-Activity RelationshipABSTRACT
Compound 1, a potent glucocorticoid receptor ligand, contains a quaternary carbon bearing trifluoromethyl and hydroxyl groups. This paper describes the effect of replacing the trifluoromethyl group on binding and agonist activity of the GR ligand 1. The results illustrate that replacing the CF3 group with a cyclohexylmethyl or benzyl group maintains the GR binding potency. These substitutions alter the functional behavior of the GR ligands from agonists to antagonists. Docking studies suggest that the benzyl analog 19 binds in a similar fashion as the GR antagonist, RU486. The central benzyl group of 19 and the C-11 dimethylaniline moiety of RU486 overlay. Binding of compound 19 is believed to force helix 12 to adopt an open conformation and this leads to the antagonist properties of the non-CF3 ligands carrying a large group at the center of the molecule.
Subject(s)
Chlorofluorocarbons, Methane/chemistry , Receptors, Glucocorticoid/agonists , Receptors, Glucocorticoid/antagonists & inhibitors , Cells, Cultured , Chlorofluorocarbons, Methane/pharmacology , Fibroblasts , HeLa Cells , Humans , Interleukin-6/biosynthesis , Interleukin-6/genetics , Ligands , Models, Molecular , Protein Binding , Protein Conformation/drug effects , Receptors, Cytoplasmic and Nuclear/drug effects , Structure-Activity Relationship , Transcription, Genetic/drug effectsABSTRACT
Histamine is critically involved in a wide range of physiological and pathological processes through its actions at different receptors. Thus, histamine receptors have been actively pursued as therapeutic targets in the pharmaceutical industry for the treatment of a variety of diseases. There are currently four histamine receptors that have been cloned, all of which are G protein-coupled receptors. Studies from both academia and pharmaceutical companies have identified compounds that modulate the function of specific histamine receptors. These efforts led to the successful introduction of histamine H(1) and H(2) receptor antagonists for the treatment of allergy and excess gastric acid secretion, respectively. Histamine H(3) receptor ligands are currently under investigation for the treatment of obesity and neurological disorders. The recently identified histamine H(4) receptor is preferentially expressed in the immune tissues, suggesting a potential role in normal immune functions and possibly in the pathogenesis of inflammatory diseases. Even with the long history of histamine research and the important applications of histamine receptor ligands, assays to measure the affinity of compounds binding to histamine receptors are still routinely analyzed using a filtration assay, a very low-throughput assay involving washing and filtration steps. This article describes a simple, robust, and homogeneous binding assay based on the scintillation proximity assay (SPA) technology that provides results equivalent to those obtained using the more complex filtration assay. The SPA format is easily adapted to high-throughput screening because it is amenable to automation. In summary, this technique allows high-throughput screening of compounds against multiple histamine receptors and, thus, facilitates drug discovery efforts.