ABSTRACT
Janus kinases (JAKs) are intracellular tyrosine kinases that mediate the signaling of numerous cytokines and growth factors involved in the regulation of immunity, inflammation, and hematopoiesis. As JAK1 pairs with JAK2, JAK3, and TYK2, a JAK1-selective inhibitor would be expected to inhibit many cytokines involved in inflammation and immune function while avoiding inhibition of the JAK2 homodimer regulating erythropoietin and thrombopoietin signaling. Our efforts began with tofacitinib, an oral JAK inhibitor approved for the treatment of rheumatoid arthritis. Through modification of the 3-aminopiperidine linker in tofacitinib, we discovered highly selective JAK1 inhibitors with nanomolar potency in a human whole blood assay. Improvements in JAK1 potency and selectivity were achieved via structural modifications suggested by X-ray crystallographic analysis. After demonstrating efficacy in a rat adjuvant-induced arthritis (rAIA) model, PF-04965842 (25) was nominated as a clinical candidate for the treatment of JAK1-mediated autoimmune diseases.
Subject(s)
Autoimmune Diseases/drug therapy , Cyclobutanes/pharmacology , Janus Kinase 1/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyrimidines/pharmacology , Pyrroles/pharmacology , Sulfonamides/pharmacology , Animals , Arthritis, Experimental/drug therapy , Cyclobutanes/chemistry , Cyclobutanes/pharmacokinetics , Cyclobutanes/therapeutic use , Dogs , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Janus Kinase 1/chemistry , Janus Kinase 2/antagonists & inhibitors , Models, Molecular , Protein Conformation , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacokinetics , Protein Kinase Inhibitors/therapeutic use , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Pyrimidines/therapeutic use , Pyrroles/chemistry , Pyrroles/pharmacokinetics , Pyrroles/therapeutic use , Rats , Substrate Specificity , Sulfonamides/chemistry , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use , Tissue DistributionABSTRACT
3-Azabicyclo[3.1.0]hexane compounds were designed as novel achiral µ opioid receptor ligands for the treatment of pruritus in dogs. In this paper, we describe the SAR of this class of opioid ligand, highlighting changes to the lead structure which led to compounds having picomolar binding affinity, selective for the µ receptor over δ and κ subtypes. Some subtleties of functional activity will also be described.
Subject(s)
Antipruritics/chemical synthesis , Bridged Bicyclo Compounds, Heterocyclic/chemical synthesis , Hexanes/chemical synthesis , Pruritus/drug therapy , Receptors, Opioid, mu/antagonists & inhibitors , Animals , Antipruritics/pharmacology , Bridged Bicyclo Compounds, Heterocyclic/pharmacology , Dogs , Guinea Pigs , Hexanes/pharmacology , Humans , In Vitro Techniques , Kinetics , Ligands , Pruritus/metabolism , Receptors, Opioid, delta/antagonists & inhibitors , Receptors, Opioid, delta/metabolism , Receptors, Opioid, kappa/antagonists & inhibitors , Receptors, Opioid, kappa/metabolism , Receptors, Opioid, mu/metabolism , Structure-Activity RelationshipABSTRACT
A concise enantioselective synthesis of the fungal metabolite ent-malbrancheamide B was accomplished through the union of a C-prenylated proline derivative and a substituted indole pyruvic acid SEM enol ether, followed by a cationic double cyclization as the key step.
Subject(s)
Chemistry, Organic/methods , Indole Alkaloids/chemical synthesis , Aldehydes/chemistry , Alkaloids/chemistry , Amides/chemistry , Biomimetic Materials/chemistry , Bridged Bicyclo Compounds/chemistry , Cations , Cyclization , Ethers/chemistry , Fungi/metabolism , Hydroxamic Acids/chemistry , Models, Chemical , Molecular Structure , StereoisomerismABSTRACT
The antimicrobial natural product chuangxinmycin has been found to be a potent and selective inhibitor of bacterial tryptophanyl tRNA synthetase (WRS). A number of analogues have been synthesised. The interaction with WRS appears to be highly constrained, as only sterically smaller analogues afforded significant inhibition. The only analogue to show inhibition comparable to chuangxinmycin also had antibacterial activity. WRS inhibition may contribute to the antibacterial action of chuangxinmycin.
Subject(s)
Anti-Bacterial Agents/pharmacology , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Staphylococcus aureus/enzymology , Tryptophan-tRNA Ligase/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Bacteria/drug effects , Enzyme Inhibitors/chemical synthesis , Hydrolysis , Indicators and Reagents , Indoles/chemical synthesis , Microbial Sensitivity Tests , Staphylococcus aureus/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In only seven steps a formal synthesis of enantiomerically enriched (+)-anatoxin-a has been achieved. This was accomplished by utilizing a highly enantioselective desymmetrization of the eight-membered ring ketone 1 to form 2, and a novel cascade reaction to construct the 9-azabicyclo[4.2.1]nonane skeleton.
