No abstract

No abstract

A novel series of N-heteroaryl 4'-(2-furyl)-4,5'-bipyrimidin-2'-amines has been identified as potent and selective A(2B) adenosine receptor antagonists. In particular, compound 5 showed high affinity for the A(2B) receptor (Ki = 17 nM), good selectivity (IC(50): A(1) > 1000 nM, A(2A) > 2500 nM, A3 > 1000 nM), displayed a favorable pharmacokinetic profile in preclinical species, and showed efficacy in functional in vitro models.

No abstract

Epidermolysis bullosa acquisita (EBA) is a rare, but prototypical, organ-specific autoimmune disease, characterized and caused by autoantibodies against type VII collagen (COL7). Mucocutaneous inflammation, blistering, and scarring are the clinical hallmarks of the disease. Treatment of EBA is difficult and mainly relies on general immunosuppression. Hence, novel treatment options are urgently needed. The phosphatidylinositol-3-kinase (PI3K) pathway is a putative target for the treatment of inflammatory diseases, including EBA. We recently discovered LAS191954, an orally available, selective PI3Kδ inhibitor. PI3Kδ has been shown to be involved in B cell and neutrophil cellular functions. Both cell types critically contribute to EBA pathogenesis, rendering LAS191954 a potential drug candidate for EBA treatment. We, here, demonstrate that LAS191954, when administered chronically, dose-dependently improved the clinical phenotype of mice harboring widespread skin lesions secondary to immunization-induced EBA. Direct comparison with high-dose corticosteroid treatment indicated superiority of LAS191954. Interestingly, levels of circulating autoantibodies were unaltered in all groups, indicating a mode of action independent of the inhibition of B cell function. In line with this, LAS191954 also hindered disease progression in antibody transfer-induced EBA, where disease develops dependent on myeloid, but independent of B cells. We further show that, in vitro, LAS191954 dose-dependently impaired activation of human myeloid cells by relevant disease stimuli. Specifically, immune complex-mediated and C5a-mediated ROS release were inhibited in a PI3Kδ-dependent manner. Accordingly, LAS191954 also modulated the dermal–epidermal separation induced in vitro by co-incubation of immune complexes with polymorph nuclear cells, thus pointing to an important role of PI3Kδ in EBA effector functions. Altogether, these results suggest a new potential mechanism for the treatment of EBA and potentially also other autoimmune bullous diseases.

BACKGROUND AND PURPOSETranslational animal models are essential in the prediction of the efficacy and side effects of new chemical entities. We have carried out a thorough study of three distinct disease-modifying antirheumatic drugs (DMARDs) in an adjuvant-induced arthritis (AIA) model in the rat and critically appraised the results in the context of the reported clinical experience in rheumatoid arthritis (RA) patients. EXPERIMENTAL APPROACHTeriflunomide -a dihydroorotate dehydrogenase (DHODH) inhibitor; AL8697 -a selective p38 MAPK inhibitor; and tofacitinib -a Janus kinase (JAK) inhibitor; were selected as representatives of their class and dose-response studies carried out using a therapeutic 10-day administration scheme in arthritic rats. Paw swelling and body weight were periodically monitored, and joint radiology and histology, lymph organ weight and haematological and biochemical parameters evaluated at study completion. KEY RESULTSAll three drugs demonstrated beneficial effects on paw swelling, bone lesions and splenomegalia, with p38 inhibition providing the best anti-inflammatory effect and JAK inhibition the best DMARD effect. Leukopenia, body weight loss and gastrointestinal toxicity were dose-dependently observed with teriflunomide treatment. p38 MAPK inhibition induced leukocytosis and increased total plasma cholesterol. JAK inhibition, normalized platelet, reticulocyte and neutrophil counts, and alanine aminotransferase (ALT) levels while inducing lymphopenia and cholesterolemia. CONCLUSIONS AND IMPLICATIONSThis multiparametric approach can reveal specific drug properties and provide translational information. Whereas the complex profile for p38 inhibition in AIA is not observed in human RA, immunosuppressants such as DHODH and JAK inhibitors show DMARD properties and side effects seen in both AIA and RA.

No abstract

The structure-activity relationships for a series of pyrazine-based A 2B adenosine receptor antagonists are described. From this work, LAS101057 (17), a potent, selective, and orally efficacious A 2B receptor antagonist, was identified as a clinical development candidate. LAS101057 inhibits agonist-induced IL-6 production in human fibroblasts and is active in an ovalbumin (OVA)-sensitized mouse model after oral administration, reducing airway hyperresponsiveness to methacholine, Th2 cytokine production, and OVA-specific IgE levels.KEYWORDS: A 2B adenosine receptor antagonist, ovalbumin mouse model, clinical candidate T he purinergic, G protein-coupled receptor A 2B has a low affinity for the endogenous mediator adenosine.1-3 Evidence published over the past decade has shown that the A 2B receptor mediates the release of inflammatory mediators from several cell types, including many which are relevant for the pathophysiology of asthma, such as mast cells, smooth muscle cells, airways epithelial cells, and fibroblasts. 4,5The A 2B receptor has a pro-inflammatory role in the gastrointestinal tract, 6 and it has been shown to contribute to the development of colitis in a murine A 2B receptor knockout model. 7Some of the initial evidence obtained using A 2B receptor knockout mice suggested an anti-inflammatory role for this receptor. 8,9 However, subsequent studies do not entirely support this concept.10-12 A 2B activates cystic fibrosis transmembrane regulator chloride channel-mediated liquid release in the lungs, 13 and it could play a role in severe watery infectious diarrhea through activation of a chloride secretory response.14 A 2B receptor knockout mice have also shown that A 2B receptor prevents endothelial damage during inflammation and stimulates endothelial cell proliferation and capillary tube formation, mediating the release of the pro-angiogenic factors VEGF, bFGF, and IGF-1, 15 suggesting a possible role in tumorigenesis.16 Expression of A 2B is upregulated in several types of cancer cells. 17,18 A 2B adenosine antagonists that have been or are in clinical trials are the dual A 2B /A 3 antagonist QAF 805 and the selective A 2B antagonist In previous disclosures, 20,21 it was revealed that appropriately substituted N-(5,6-diarylpyridin-2-yl)amides are potent and selective A 2B adenosine receptor antagonists. Although particular compounds from these series demonstrated good oral bioavailability in rat pharmacokinetic studies, in general all compounds tested presented rapid systemic clearance.Herein are detailed further optimization efforts in a structurally related series which ultimately led to the discovery of a clinical candidate LAS101057 (17) intended for use in oral asthma therapy.Studies conducted in parallel to those described above revealed that replacement of the central pyridine scaffold of compounds from the amide-based series by a pyrazine moiety gave compounds with good activity/selectivity profiles ( Table 1).The pharmacokinetic profiles of the pyrazines 1 and 2 in the rat were ...