ABSTRACT
Tyrosine kinase 2 (TYK2) is a nonreceptor tyrosine kinase that belongs to the JAK family also comprising JAK1, JAK2, and JAK3. TYK2 is an attractive target for various autoimmune diseases as it regulates signal transduction downstream of IL-23 and IL-12 receptors. Selective TYK2 inhibition offers a differentiated clinical profile compared to currently approved JAK inhibitors. However, selectivity for TYK2 versus other JAK family members has been difficult to achieve with small molecules that inhibit the catalytically active kinase domain. Successful targeting of the TYK2 pseudokinase domain as a strategy to achieve isoform selectivity was recently exemplified with deucravacitinib. Described herein is the optimization of selective TYK2 inhibitors targeting the pseudokinase domain, resulting in the discovery of the clinical candidate ABBV-712 (21).
Subject(s)
Autoimmune Diseases , TYK2 Kinase , Humans , Janus KinasesABSTRACT
We report a DNA-compatible protocol for synthesizing amides from DNA-bound aldehydes and non-nucleophilic arylamines including aza-substituted anilines, 2-aminobenzimidazoles, and 3-aminopyrazoles. The reactions were carried out at room temperature and provided reasonable conversions and wide functional group compatibility. The reactions were also successful when employing aryl and aliphatic aldehydes. In addition, qPCR and NGS data suggested no negative impact on DNA integrity after the copper-mediated oxidative amidation reaction.
Subject(s)
Aldehydes/chemistry , Amides/chemistry , Amines/chemistry , Copper/chemistry , DNA/chemistry , Aldehydes/chemical synthesis , Amides/chemical synthesis , Aniline Compounds/chemistry , Catalysis , Oxidation-ReductionABSTRACT
Blockade of interleukin (IL)-23 or IL-17 with biologics is clinically validated as a treatment of psoriasis. However, the clinical impact of targeting other nodes within the IL-23/IL-17 pathway, especially with small molecules, is less defined. We report on a novel small molecule inverse agonist of retinoid acid-related orphan receptor (ROR) γt and its efficacy in preclinical models of psoriasis and arthritis. 1-(2,4-Dichloro-3-((1,4-dimethyl-6-(trifluoromethyl)-1H-indol-2-yl)methyl)benzoyl)piperidine-4-carboxylic acid (A-9758) was optimized from material identified from a high-throughput screening campaign. A-9758 is selective for RORγt and exhibits robust potency against IL-17A release both in vitro and in vivo. In vivo, we also show that IL-23 is sufficient to drive the accumulation of RORγt+ cells, and inhibition of RORγt significantly attenuates IL-23-driven psoriasiform dermatitis. Therapeutic treatment with A-9758 (i.e., delivered during active disease) was also effective in blocking skin and joint inflammation. Finally, A-9758 exhibited efficacy in an ex vivo human whole blood assay, suggesting small molecule inverse agonists of RORγt could be efficacious in human IL-17-related diseases. SIGNIFICANCE STATEMENT: Using a novel small molecule inverse agonist, and preclinical assays, we show that RORγt is a viable target for the inhibition of RORγt/Th17-driven diseases such as psoriasis. Preclinical models of psoriasis show that inhibition of RORγt blocks both the accumulation and effector function of IL-17-producing T cells.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Arthritis/drug therapy , Interleukin-23/metabolism , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Piperidines/pharmacology , Psoriasis/drug therapy , Animals , Anti-Inflammatory Agents/pharmacology , COS Cells , Cells, Cultured , Chlorocebus aethiops , Female , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Piperidines/therapeutic useABSTRACT
A high-throughput screen against Inventiva's compound library using a Gal4/RORγ-LBD luciferase reporter gene assay led to the discovery of a new series of quinoline sulphonamides as RORγ inhibitors, eventually giving rise to a lead compound having an interesting in vivo profile after oral administration. This lead was evaluated in a target engagement model in mouse, where it reduced IL-17 cytokine production after immune challenge. It also proved to be active in a multiple sclerosis model (EAE) where it reduced the disease score. The synthesis, structure activity relationship (SAR) and biological activity of these derivatives is described herein.
Subject(s)
Drug Inverse Agonism , Nuclear Receptor Subfamily 1, Group F, Member 3/chemistry , Quinolines/chemistry , Animals , Disease Models, Animal , Humans , MiceABSTRACT
We previously demonstrated that selective inhibition of protein kinase Cθ (PKCθ) with triazinone 1 resulted in dose-dependent reduction of paw swelling in a mouse model of arthritis.1,2 However, a high concentration was required for efficacy, thus providing only a minimal safety window. Herein we describe a strategy to deliver safer compounds based on the hypothesis that optimization of potency in concert with good oral pharmacokinetic (PK) properties would enable in vivo efficacy at reduced exposures, resulting in an improved safety window. Ultimately, transformation of 1 yielded analogues that demonstrated excellent potency and PK properties and fully inhibited IL-2 production in an acute model. In spite of good exposure, twice-a-day treatment with 17l in the glucose-6-phosphate isomerase chronic in vivo mouse model of arthritis yielded only moderate efficacy. On the basis of the exposure achieved, we conclude that PKCθ inhibition alone is insufficient for complete efficacy in this rodent arthritis model.
Subject(s)
Anti-Inflammatory Agents/pharmacology , Arthritis, Experimental/drug therapy , Isoenzymes/antagonists & inhibitors , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Animals , Anti-Inflammatory Agents/chemistry , Anti-Inflammatory Agents/metabolism , Arthritis, Experimental/metabolism , Crystallography, X-Ray , Disease Models, Animal , Humans , Interleukin-2/metabolism , Isoenzymes/chemistry , Isoenzymes/metabolism , Male , Mice , Models, Chemical , Models, Molecular , Molecular Structure , Protein Binding , Protein Kinase C/chemistry , Protein Kinase C/metabolism , Protein Kinase C-theta , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/metabolism , Protein Structure, Tertiary , Treatment OutcomeABSTRACT
Protein kinase Cθ (PKCθ) regulates a key step in the activation of T cells. On the basis of its mechanism of action, inhibition of this kinase is hypothesized to serve as an effective therapy for autoimmune diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and psoriasis. Herein, the discovery of a small molecule PKCθ inhibitor is described, starting from a fragment hit 1 and advancing to compound 41 through the use of structure-based drug design. Compound 41 demonstrates excellent in vitro activity, good oral pharmacokinetics, and efficacy in both an acute in vivo mechanistic model and a chronic in vivo disease model but suffers from tolerability issues upon chronic dosing.
Subject(s)
Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Protein Kinase C/antagonists & inhibitors , Protein Kinase C/chemistry , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Administration, Oral , Animals , Area Under Curve , Arthritis, Experimental/drug therapy , Biological Availability , Cells, Cultured , Chromatography, Liquid , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Design , Drug Discovery , Female , Humans , Isoenzymes/metabolism , Mass Spectrometry , Mice, Inbred BALB C , Mice, Inbred DBA , Models, Molecular , Molecular Structure , Protein Binding , Protein Kinase C/metabolism , Protein Kinase C-theta , Protein Kinase Inhibitors/pharmacokinetics , Protein Structure, Tertiary , Rats , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacokinetics , Small Molecule Libraries/pharmacology , T-Lymphocytes/drug effectsABSTRACT
Modification of a 2-iminobenzimidazole series derived from an HTS hit resulted in compounds with improved in-vitro species selectivity. Incorporation of an 8-quinoline amide and conformational rigidification of an aliphatic tether furnished potent compounds suitable for further lead optimization.