ABSTRACT
Systemic lupus erythematosus (SLE) is associated with an IL-2-deficient state, with regulatory T cells (Tregs) showing diminished immune regulatory capacity. A low dose of IL-2 has shown encouraging clinical benefits in SLE patients; however, its clinical utility is limited because of the requirement of daily injections and the observation of increase in proinflammatory cytokines and in non-Tregs. We recently showed that a fusion protein of mouse IL-2 and mouse IL-2Rα (CD25), joined by a noncleavable linker, was effective in treating diabetes in NOD mice by selectively inducing Treg expansion. In this report, we show that mouse IL-2 (mIL-2)/CD25 at doses up to 0.5 mg/kg twice a week induced a robust Treg expansion without showing signs of increase in the numbers of NK, CD4+Foxp3-, or CD8+ T cells or significant increase in proinflammatory cytokines. In both NZB × NZW and MRL/lpr mice, mIL-2/CD25 at 0.2-0.4 mg/kg twice a week demonstrated efficacy in inducing Treg expansion, CD25 upregulation, and inhibiting lupus nephritis based on the levels of proteinuria, autoantibody titers, and kidney histology scores. mIL-2/CD25 was effective even when treatment was initiated at the time when NZB × NZW mice already showed signs of advanced disease. Furthermore, we show coadministration of prednisolone, which SLE patients commonly take, did not interfere with the ability of mIL-2/CD25 to expand Tregs. The prednisolone and mIL-2/CD25 combination treatment results in improvements in most of the efficacy readouts relative to either monotherapy alone. Taken together, our results support further evaluation of IL-2/CD25 in the clinic for treating immune-mediated diseases such as SLE.
Subject(s)
Lupus Erythematosus, Systemic , T-Lymphocytes, Regulatory , Animals , CD8-Positive T-Lymphocytes , Forkhead Transcription Factors , Humans , Interleukin-2 , Interleukin-2 Receptor alpha Subunit , Lupus Erythematosus, Systemic/drug therapy , Mice , Mice, Inbred MRL lpr , Mice, Inbred NODABSTRACT
BACKGROUND: Signalling through platelet-derived growth factor receptor (PDGFR), colony-stimulating factor 1 receptor (CSF1R) and mast/stem cell growth factor receptor kit (c-KIT) plays a critical role in pulmonary arterial hypertension (PAH). We examined the preclinical efficacy of inhaled seralutinib, a unique small-molecule PDGFR/CSF1R/c-KIT kinase inhibitor in clinical development for PAH, in comparison to a proof-of-concept kinase inhibitor, imatinib. METHODS: Seralutinib and imatinib potency and selectivity were compared. Inhaled seralutinib pharmacokinetics/pharmacodynamics were studied in healthy rats. Efficacy was evaluated in two rat models of PAH: SU5416/Hypoxia (SU5416/H) and monocrotaline pneumonectomy (MCTPN). Effects on inflammatory/cytokine signalling were examined. PDGFR, CSF1R and c-KIT immunohistochemistry in rat and human PAH lung samples and microRNA (miRNA) analysis in the SU5416/H model were performed. RESULTS: Seralutinib potently inhibited PDGFRα/ß, CSF1R and c-KIT. Inhaled seralutinib demonstrated dose-dependent inhibition of lung PDGFR and c-KIT signalling and increased bone morphogenetic protein receptor type 2 (BMPR2). Seralutinib improved cardiopulmonary haemodynamic parameters and reduced small pulmonary artery muscularisation and right ventricle hypertrophy in both models. In the SU5416/H model, seralutinib improved cardiopulmonary haemodynamic parameters, restored lung BMPR2 protein levels and decreased N-terminal pro-brain natriuretic peptide (NT-proBNP), more than imatinib. Quantitative immunohistochemistry in human lung PAH samples demonstrated increased PDGFR, CSF1R and c-KIT. miRNA analysis revealed candidates that could mediate seralutinib effects on BMPR2. CONCLUSIONS: Inhaled seralutinib was an effective treatment of severe PAH in two animal models, with improved cardiopulmonary haemodynamic parameters, a reduction in NT-proBNP, reverse remodelling of pulmonary vascular pathology and improvement in inflammatory biomarkers. Seralutinib showed greater efficacy compared to imatinib in a preclinical study.
Subject(s)
Hypertension, Pulmonary , MicroRNAs , Pulmonary Arterial Hypertension , Rats , Humans , Animals , Imatinib Mesylate/pharmacology , Imatinib Mesylate/metabolism , Imatinib Mesylate/therapeutic use , Monocrotaline , Familial Primary Pulmonary Hypertension , Pulmonary Artery , Protein Kinase Inhibitors/pharmacology , Protein Kinase Inhibitors/therapeutic use , Hypoxia , MicroRNAs/metabolism , Disease Models, AnimalABSTRACT
The role of retinoid-related orphan receptor γ t (RORγt) in Th17 cell differentiation has been well established; however, how it regulates other T cell lineages is still not clearly understood. In this study, we report that in mice, while promoting Th17 cell differentiation, RORγt inhibited IL-10 production by T cells, thereby preserving the pathogenicity of Th17 cells. Treatment with RORγt-specific inhibitor suppressed Th17 cell signature cytokines, but promoted IL-10 production. RORγt inhibitor-treated Th17 cells induce less severe colitis compared with control Th17 cells. Mechanistically, the RORγt inhibitor induced T cell expression of Blimp-1 (encoded by Prdm1). Prdm1-/- T cells produced significantly fewer IL-10 when treated with RORγt inhibitor compared with wild-type T cells. Furthermore, RORγt inhibitor-treated Prdm1-/- Th17 cells induce more severe colitis compared with RORγt inhibitor-treated wild-type Th17 cells. Collectively, our studies reveal a novel mechanism by which RORγt drives and maintains pathogenic Th17 cell development by inhibiting IL-10 production.
Subject(s)
Colitis/immunology , Interleukin-10/metabolism , Intestines/immunology , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Th17 Cells/immunology , Animals , Cell Differentiation , Cell Lineage , Cells, Cultured , Epigenetic Repression , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Knockout , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Positive Regulatory Domain I-Binding Factor 1/geneticsABSTRACT
In an effort to discover oral inverse agonists of RORγt to treat inflammatory diseases, a new 2,6-difluorobenzyl ether series of cyclopentyl sulfones were found to be surprisingly more potent than the corresponding alcohol derivatives. When combined with a more optimized phenyl ((R)-3-phenylpyrrolidin-3-yl)sulfone template, the 2,6-difluorobenzyl ethers yielded a set of very potent RORγt inverse agonists (e.g., compound 26, RORγt Gal4 EC50 11 nM) that are highly selective against PXR, LXRα and LXRß. After optimizing for stability in human and mouse liver microsomes, compounds 29 and 38 were evaluated in vivo and found to have good oral bioavailability (56% and 101%, respectively) in mice. X-ray co-crystal structure of compound 27 in RORγt revealed that the bulky benzyl ether group causes helix 11 of the protein to partially uncoil to create a new, enlarged binding site, which nicely accommodates the benzyl ether moiety, leading to net potency gain.
Subject(s)
Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Pyrrolidines/pharmacology , Sulfones/pharmacology , Animals , Crystallography, X-Ray , Drug Discovery , Drug Inverse Agonism , Drug Stability , Hep G2 Cells , Humans , Mice , Microsomes, Liver/metabolism , Molecular Structure , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/metabolism , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/metabolismABSTRACT
A novel series of cis-3,4-diphenylpyrrolidines were designed as RORγt inverse agonists based on the binding conformation of previously reported bicyclic sulfonamide 1. Preliminary synthesis and structure-activity relationship (SAR) study established (3S,4S)-3-methyl-3-(4-fluorophenyl)-4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxyprop-2-yl)phenyl)pyrrolidine as the most effective scaffold. Subsequent SAR optimization led to identification of a piperidinyl carboxamide 31, which was potent against RORγt (EC50 of 61 nM in an inverse agonist assay), selective relative to RORα, RORß, LXRα and LXRß, and stable in human and mouse liver microsomes. Furthermore, compound 31 exhibited considerably lower PXR Ymax (46%) and emerged as a promising lead. The binding mode of the diphenylpyrrolidine series was established with an X-ray co-crystal structure of 10A/RORγt.
Subject(s)
Drug Design , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Pyrrolidines/chemistry , Animals , Binding Sites , Crystallography, X-Ray , Drug Inverse Agonism , Humans , Mice , Microsomes, Liver/metabolism , Molecular Dynamics Simulation , Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Pregnane X Receptor/agonists , Pregnane X Receptor/metabolism , Pyrrolidines/chemical synthesis , Pyrrolidines/metabolism , Structure-Activity RelationshipABSTRACT
In order to rapidly develop C6 and C8 SAR of our reported tricyclic sulfone series of RORγt inverse agonists, a late-stage bromination was employed. Although not regioselective, the bromination protocol allowed us to explore new substitution patterns/vectors that otherwise would have to be incorporated at the very beginning of the synthesis. Based on the SAR obtained from this exercise, compound 15 bearing a C8 fluorine was developed as a very potent and selective RORγt inverse agonist. This analog's in vitro profile, pharmacokinetic (PK) data and efficacy in an IL-23 induced mouse acanthosis model will be discussed.
Subject(s)
Heterocyclic Compounds, 3-Ring/therapeutic use , Melanosis/drug therapy , Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors , Sulfones/therapeutic use , Animals , Crystallography, X-Ray , Drug Inverse Agonism , Female , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/pharmacokinetics , Interleukin-18 , Male , Melanosis/chemically induced , Mice, Inbred BALB C , Mice, Inbred C57BL , Molecular Structure , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Protein Binding , Structure-Activity Relationship , Sulfones/chemical synthesis , Sulfones/pharmacokineticsABSTRACT
An X-ray crystal structure of one of our previously discovered RORγt inverse agonists bound to the RORγt ligand binding domain revealed that the cyclohexane carboxylic acid group of compound 2 plays a significant role in RORγt binding, forming four hydrogen bonding and ionic interactions with RORγt. SAR studies centered around the cyclohexane carboxylic acid group led to identification of several structurally diverse and more potent compounds, including new carboxylic acid analogues 7 and 20, and cyclic sulfone analogues 34 and 37. Notably, compounds 7 and 20 were found to maintain the desirable pharmacokinetic profile of 2.
Subject(s)
Nuclear Receptor Subfamily 1, Group F, Member 3/agonists , Pyrrolidines/pharmacology , Sulfones/pharmacology , Administration, Oral , Animals , Biological Availability , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Inverse Agonism , Humans , Mice , Models, Molecular , Molecular Structure , Pyrrolidines/administration & dosage , Pyrrolidines/chemistry , Structure-Activity Relationship , Sulfones/administration & dosage , Sulfones/chemistryABSTRACT
We disclose the optimization of a high throughput screening hit to yield benzothiazine and tetrahydroquinoline sulfonamides as potent RORγt inverse agonists. However, a majority of these compounds showed potent activity against pregnane X receptor (PXR) and modest activity against liver X receptor α (LXRα). Structure-based drug design (SBDD) led to the identification of benzothiazine and tetrahydroquinoline sulfonamide analogs which completely dialed out LXRα activity and were less potent at PXR. Pharmacodynamic (PD) data for compound 35 in an IL-23 induced IL-17 mouse model is discussed along with the implications of a high Ymax in the PXR assay for long term preclinical pharmacokinetic (PK) studies.
Subject(s)
Bridged Bicyclo Compounds/pharmacology , Drug Design , Propanols/pharmacology , Receptors, Retinoic Acid/agonists , Receptors, Steroid/agonists , Sulfonamides/pharmacology , Animals , Bridged Bicyclo Compounds/chemical synthesis , Bridged Bicyclo Compounds/chemistry , Crystallography, X-Ray , Dose-Response Relationship, Drug , Humans , Liver X Receptors/agonists , Male , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Pregnane X Receptor , Propanols/chemical synthesis , Propanols/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistry , Retinoic Acid Receptor gammaABSTRACT
A series of potent dual JAK1/3 inhibitors have been developed from a moderately selective JAK3 inhibitor. Substitution at the C6 position of the pyrrolopyridazine core with aryl groups provided exceptional biochemical potency against JAK1 and JAK3 while maintaining good selectivity against JAK2 and Tyk2. Translation to in vivo efficacy was observed in a murine model of chronic inflammation. X-ray co-crystal structure determination confirmed the presumed inhibitor binding orientation in JAK3. Efforts to reduce hERG channel inhibition will be described.
Subject(s)
Janus Kinase 1/antagonists & inhibitors , Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Pyridazines/chemistry , Pyrroles/chemistry , Animals , Binding Sites , Catalytic Domain , Cell Line , Crystallography, X-Ray , Disease Models, Animal , Drug Evaluation, Preclinical , Half-Life , Humans , Inflammation/prevention & control , Inhibitory Concentration 50 , Janus Kinase 1/metabolism , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Janus Kinase 3/metabolism , Mice , Mice, Inbred BALB C , Molecular Conformation , Molecular Dynamics Simulation , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/pharmacokinetics , Pyridazines/chemical synthesis , Pyridazines/pharmacokinetics , Pyrroles/chemical synthesis , Pyrroles/pharmacokinetics , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , TYK2 Kinase/antagonists & inhibitors , TYK2 Kinase/metabolismABSTRACT
As demonstrated in preclinical animal models, the disruption of PI3Kδ expression or its activity leads to a decrease in inflammatory and immune responses. Therefore, inhibition of PI3Kδ may provide an alternative treatment for autoimmune diseases, such as RA, SLE, and respiratory ailments. Herein, we disclose the identification of 7-(3-(piperazin-1-yl)phenyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine derivatives as highly potent, selective and orally bioavailable PI3Kδ inhibitors. The lead compound demonstrated efficacy in an in vivo mouse KLH model.
Subject(s)
Amines/chemistry , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Amines/metabolism , Amines/therapeutic use , Animals , Autoimmune Diseases/drug therapy , Binding Sites , Class I Phosphatidylinositol 3-Kinases , Crystallography, X-Ray , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Mice , Microsomes, Liver/metabolism , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Piperazine , Piperazines/chemistry , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/therapeutic use , Structure-Activity Relationship , Triazines/chemistryABSTRACT
A useful and novel set of tool molecules have been identified which bind irreversibly to the JAK3 active site cysteine residue. The design was based on crystal structure information and a comparative study of several electrophilic warheads.
Subject(s)
Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Binding Sites , Catalytic Domain , Cell Line , Cell Survival/drug effects , Drug Evaluation, Preclinical , Humans , Inhibitory Concentration 50 , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/metabolism , Janus Kinase 3/metabolism , Molecular Docking Simulation , Protein Kinase Inhibitors/metabolism , Structure-Activity RelationshipABSTRACT
Aberrant Class I PI3K signaling is a key factor contributing to many immunological disorders and cancers. We have identified 4-amino pyrrolotriazine as a novel chemotype that selectively inhibits PI3Kδ signaling despite not binding to the specificity pocket of PI3Kδ isoform. Structure activity relationship (SAR) led to the identification of compound 30 that demonstrated efficacy in mouse Keyhole Limpet Hemocyanin (KLH) and collagen induced arthritis (CIA) models.
Subject(s)
Amines/chemistry , Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemistry , Triazines/chemistry , Amines/metabolism , Amines/therapeutic use , Animals , Arthritis/drug therapy , Arthritis/metabolism , Arthritis/pathology , Binding Sites , Disease Models, Animal , Drug Evaluation, Preclinical , Inhibitory Concentration 50 , Mice , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Protein Binding , Protein Isoforms/antagonists & inhibitors , Protein Isoforms/metabolism , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/therapeutic use , Protein Structure, Tertiary , Structure-Activity RelationshipABSTRACT
The synthesis and structure-activity relationship (SAR) of a series of pyridyl-isoxazole based agonists of S1P1 are discussed. Compound 5b provided potent in vitro activity with selectivity, had an acceptable pharmacokinetic profile, and demonstrated efficacy in a dose dependent manner when administered orally in a rodent model of arthritis.
Subject(s)
Arthritis, Experimental/drug therapy , Lysophospholipids/agonists , Sphingosine/analogs & derivatives , Structure-Activity Relationship , Administration, Oral , Animals , Chemistry Techniques, Synthetic , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Humans , Isoxazoles/chemistry , Isoxazoles/pharmacology , Lymphocyte Count , Male , Rats, Inbred Lew , Receptors, Lysosphingolipid/agonists , Sphingosine/agonistsABSTRACT
CD40-CD40L interactions play a critical role in regulating immune responses. Blockade of CD40L by Abs, such as the anti-CD40L Ab 5c8, demonstrated positive clinical effects in patients with autoimmune diseases; however, incidents of thromboembolism (TE) precluded further development of these molecules. In this study, we examined the role of the Fc domain interaction with FcγRs in modulating platelet activation and potential for TE. Our results show that the interaction of the 5c8 wild-type IgG1 Fc domain with FcγRs is responsible for platelet activation, as measured by induction of PAC-1 and CD62P. A version of 5c8 with a mutated IgG1 tail was identified that showed minimal FcγR binding and platelet activation while maintaining full binding to CD40L. To address whether Fc effector function is required for immunosuppression, a potent Ab fragment, termed a "domain Ab" (dAb), against murine CD40L was identified and fused to a murine IgG1 Fc domain containing a D265A mutation that lacks Fc effector function. In vitro, this dAb-Fc demonstrated comparable potency to the benchmark mAb MR-1 in inhibiting B cell and dendritic cell activation. Furthermore, the anti-CD40L dAb-Fc exhibited a notable efficacy comparable to MR-1 in various preclinical models, such as keyhole limpet hemocyanin-induced Ab responses, alloantigen-induced T cell proliferation, "heart-to-ear" transplantation, and NZB × NZW F1 spontaneous lupus. Thus, our data show that immunosuppression and TE can be uncoupled and that a CD40L dAb with an inert Fc tail is expected to be efficacious for treating autoimmune diseases, with reduced risk for TE.
Subject(s)
Autoimmune Diseases/immunology , CD40 Ligand/immunology , Platelet Activation/drug effects , Single-Domain Antibodies/pharmacology , Animals , Antibodies, Monoclonal/adverse effects , Disease Models, Animal , HEK293 Cells , Humans , Lymphocyte Activation/drug effects , Lymphocyte Activation/immunology , Mice , Platelet Activation/immunology , Receptors, IgG/immunology , Single-Domain Antibodies/immunology , Surface Plasmon Resonance , Thromboembolism/etiology , Thromboembolism/prevention & control , TransfectionABSTRACT
Therapies targeting either interleukin (IL)-23 or IL-17 have shown promise in treating T helper 17 (Th17)-driven autoimmune diseases. Although IL-23 is a critical driver of IL-17, recognition of nonredundant and independent functions of IL-23 and IL-17 has prompted the notion that dual inhibition of both IL-23 and IL-17 could offer even greater efficacy for treating autoimmune diseases relative to targeting either cytokine alone. To test this hypothesis, we generated selective inhibitors of IL-23 and IL-17 and tested the effect of either treatment alone compared with their combination in vitro and in vivo. In vitro, using a novel culture system of murine Th17 cells and NIH/3T3 fibroblasts, we showed that inhibition of both IL-23 and IL-17 completely suppressed IL-23-dependent IL-22 production from Th17 cells and cooperatively blocked IL-17-dependent IL-6 secretion from the NIH/3T3 cells to levels below either inhibitor alone. In vivo, in the imiquimod induced skin inflammation model, and in the myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis model, we demonstrated that dual inhibition of IL-17 and IL-23 was more efficacious in reducing disease than targeting either cytokine alone. Together, these data support the hypothesis that neutralization of both IL-23 and IL-17 may provide enhanced benefit against Th17 mediated autoimmunity and provide a basis for a therapeutic strategy aimed at dual targeting IL-23 and IL-17.
Subject(s)
Autoimmunity/immunology , Encephalomyelitis, Autoimmune, Experimental/immunology , Interleukin-17/antagonists & inhibitors , Interleukin-17/immunology , Interleukin-23/antagonists & inhibitors , Interleukin-23/immunology , Animals , Antibodies, Monoclonal/pharmacology , Antibodies, Monoclonal/therapeutic use , Autoimmunity/drug effects , Coculture Techniques , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Female , HEK293 Cells , Humans , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , NIH 3T3 Cells , Random AllocationABSTRACT
OBJECTIVE: Interferon-γ-inducible protein-10 (IP-10 or CXCL10) plays a role in inflammatory cell migration and epithelial cell survival and migration. It is expressed in higher levels in the colonic tissue and plasma of patients with ulcerative colitis (UC). This phase II study assessed the efficacy and safety of BMS-936557, a fully human, monoclonal antibody to IP-10, in the treatment of moderately-to-severely active UC. DESIGN: In this 8-week, phase II, double-blind, multicentre, randomised study, patients with active UC received placebo or BMS-936557 (10 mg/kg) intravenously every other week. The primary endpoint was the rate of clinical response at Day 57; clinical remission and mucosal healing rates were secondary endpoints. Post hoc analyses evaluated the drug exposure-response relationship and histological improvement. RESULTS: 109 patients were included (BMS-936557: n=55; placebo: n=54). Prespecified primary and secondary endpoints were not met; clinical response rate at Day 57 was 52.7% versus 35.2% for BMS-936557 versus placebo (p=0.083), and clinical remission and mucosal healing rates were 18.2% versus 16.7% (p=1.00) and 41.8% versus 35.2% (p=0.556), respectively. However, higher BMS-936557 steady-state trough concentration (Cminss) was associated with increased clinical response (87.5% vs 37.0% (p<0.001) for patients with Cminss 108-235 µg/ml vs placebo) and histological improvements (73.0% vs 41.0%; p=0.004). Infections occurred in 7 (12.7%) BMS-936557-treated patients and 3 (5.8%) placebo-treated patients. 2 (3.6%) BMS-936557 patients discontinued due to adverse events. CONCLUSIONS: Anti-IP-10 antibody, BMS-936557, is a potentially effective therapy for moderately-to-severely active UC. Higher drug exposure correlated with increasing clinical response and histological improvement. Further dose-response studies are warranted. CLINICAL TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT00656890.
Subject(s)
Anti-Inflammatory Agents/therapeutic use , Antibodies, Monoclonal/therapeutic use , Chemokine CXCL10/antagonists & inhibitors , Colitis, Ulcerative/drug therapy , Induction Chemotherapy , Administration, Intravenous , Adolescent , Adult , Aged , Aged, 80 and over , Colitis, Ulcerative/pathology , Double-Blind Method , Drug Administration Schedule , Female , Humans , Intention to Treat Analysis , Logistic Models , Male , Middle Aged , Severity of Illness Index , Treatment Outcome , Young AdultABSTRACT
Acylureas and acyclic imides are found to be excellent isosteres for 2-acylamino-1,3,4-thiadiazole in the azaxanthene-based series of glucocorticoid receptor (GR) agonists. The results reported herein show that primary acylureas maintain high affinity and selectivity for GR while providing improved CYP450 inhibition and pharmacokinetic profile over 2-acylamino-1,3,4-thiadiazoles. General methods for synthesis of a variety of acylureas and acyclic imides from a carboxylic acid were utilized and are described.
Subject(s)
Drug Discovery , Heterocyclic Compounds, 3-Ring/pharmacology , Receptors, Glucocorticoid/agonists , Thiadiazoles/pharmacology , Urea/pharmacology , Crystallography, X-Ray , Dose-Response Relationship, Drug , Heterocyclic Compounds, 3-Ring/chemical synthesis , Heterocyclic Compounds, 3-Ring/chemistry , Humans , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Thiadiazoles/chemistry , Urea/analogs & derivatives , Urea/chemistryABSTRACT
A new class of Janus kinase (JAK) inhibitors was discovered using a rationally designed pyrrolo[1,2-b]pyridazine-3-carboxamide scaffold. Preliminary studies identified (R)-(2,2-dimethylcyclopentyl)amine as a preferred C4 substituent on the pyrrolopyridazine core (3b). Incorporation of amino group to 3-position of the cyclopentane ring resulted in a series of JAK3 inhibitors (4g-4j) that potently inhibited IFNγ production in an IL2-induced whole blood assay and displayed high functional selectivity for JAK3-JAK1 pathway relative to JAK2. Further modifications led to the discovery of an orally bioavailable (2-fluoro-2-methylcyclopentyl)amino analogue 5g which is a nanomolar inhibitor of both JAK3 and TYK2, functionally selective for the JAK3-JAK1 pathway versus JAK2, and active in a human whole blood assay.
Subject(s)
Drug Discovery , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 3/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Pyridazines/chemistry , Pyrroles/chemistry , Administration, Oral , Animals , Enzyme-Linked Immunosorbent Assay , Humans , Interferon-gamma/metabolism , Mice , Mice, Inbred BALB C , Models, Molecular , Molecular Structure , Protein Conformation/drug effects , Protein Kinase Inhibitors/administration & dosage , Protein Kinase Inhibitors/pharmacokinetics , Structure-Activity Relationship , Tissue DistributionABSTRACT
BACKGROUND & AIMS: The efficacy of abatacept, a selective costimulation modulator, in Crohn's disease (CD) and ulcerative colitis (UC) is unknown. METHODS: Four placebo-controlled trials evaluated the efficacy and safety of abatacept as induction (IP) and maintenance (MP) therapy in adults with active, moderate-to-severe CD (CD-IP; CD-MP) and UC (UC-IP1; UC-MP). In CD-IP and UC-IP1, 451 patients with CD and 490 patients with UC were randomized to abatacept 30, 10, or 3 mg/kg (according to body weight) or placebo, and dosed at weeks 0, 2, 4, and 8. In MP, 90 patients with CD and 131 patients with UC who responded to abatacept at week 12 in the induction trials were randomized to abatacept 10 mg/kg or placebo every 4 weeks through week 52. RESULTS: In CD-IP, 17.2%, 10.2%, and 15.5% of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at weeks 8 and 12, vs 14.4% receiving placebo (P = .611, P = .311, and P = .812, respectively). In UC-IP1, 21.4%, 19.0%, and 20.3% of patients receiving abatacept 30, 10, and 3 mg/kg achieved a clinical response at week 12, vs 29.5% receiving placebo (P = .124, P = .043, and P = .158, respectively). In CD-MP, 23.8% vs 11.1% of abatacept vs placebo patients were in remission at week 52. In UC-MP, 12.5% vs 14.1% of patients receiving abatacept vs placebo were in remission at week 52. Safety generally was comparable between groups. CONCLUSIONS: The studies showed that abatacept is not efficacious for the treatment of moderate-to-severe CD or UC.