ABSTRACT
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 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
The lymphocyte-specific kinase (Lck) is a cytoplasmic tyrosine kinase of the Src family expressed in T cells and NK cells. Genetic evidence in both mice and humans demonstrates that Lck kinase activity is critical for signaling mediated by the T cell receptor (TCR), which leads to normal T cell development and activation. A small molecule inhibitor of Lck is expected to be useful in the treatment of T cell-mediated autoimmune and inflammatory disorders and/or organ transplant rejection. In this paper, we describe the synthesis, structure-activity relationships, and pharmacological characterization of 2-aminopyrimidine carbamates, a new class of compounds with potent and selective inhibition of Lck. The most promising compound of this series, 2,6-dimethylphenyl 2-((3,5-bis(methyloxy)-4-((3-(4-methyl-1-piperazinyl)propyl)oxy)phenyl)amino)-4-pyrimidinyl(2,4-bis(methyloxy)phenyl)carbamate (43) exhibits good activity when evaluated in in vitro assays and in an in vivo model of T cell activation.
Subject(s)
Aminopyridines/chemical synthesis , Anti-Inflammatory Agents/chemical synthesis , Carbamates/chemical synthesis , Lymphocyte Specific Protein Tyrosine Kinase p56(lck)/antagonists & inhibitors , Pyrimidines/chemical synthesis , Administration, Oral , Aminopyridines/chemistry , Aminopyridines/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/pharmacology , Biological Availability , Carbamates/chemistry , Carbamates/pharmacology , Crystallography, X-Ray , Humans , In Vitro Techniques , Jurkat Cells , Lymphocyte Activation , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Pyrimidines/chemistry , Pyrimidines/pharmacology , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
High-throughput screening against the human sirtuin SIRT1 led to the discovery of a series of indoles as potent inhibitors that are selective for SIRT1 over other deacetylases and NAD-processing enzymes. The most potent compounds described herein inhibit SIRT1 with IC50 values of 60-100 nM, representing a 500-fold improvement over previously reported SIRT inhibitors. Preparation of enantiomerically pure indole derivatives allowed for their characterization in vitro and in vivo. Kinetic analyses suggest that these inhibitors bind after the release of nicotinamide from the enzyme and prevent the release of deacetylated peptide and O-acetyl-ADP-ribose, the products of enzyme-catalyzed deacetylation. These SIRT1 inhibitors are low molecular weight, cell-permeable, orally bioavailable, and metabolically stable. These compounds provide chemical tools to study the biology of SIRT1 and to explore therapeutic uses for SIRT1 inhibitors.
