pyrimidinones and ulodesine

To update recent developments in medications targeting hyperuricemia, but not including medications recently labelled in the European Union and the United States.. A new xanthine oxidase inhibitor, Topiloric (Fujiyakuhin Co., Ltd. Japan) Uriadec (Sanwa Kagaku Kenkyusho Co., Ltd. Japan), has been developed and labelled in Japan. An inhibitor of purine nucleoside phosphorylase, Ulodesine, is in development in combination with allopurinol. The rest of the medications in the pipeline for hyperuricemia are targeting renal transporters of uric acid, mainly URAT1 and OAT4, acting as uricosuric agents. Most of them, such as lesinurad and arhalofenate, are being tested in trials in combination with allopurinol and febuxostat. The most potent RDEA3170 is being tested in monotherapy, but also associated with febuxostat. Recently, medications showing dual activity, inhibiting both xanthine oxidoreductase and URAT1, have been communicated or started exploratory clinical trials. There is no report of medications targeting other transporters such as Glut9 or ABCG2.. There are a number of medications in the pipeline targeting hyperuricemia, mostly uricosurics in combination with xanthine oxidase inhibitors, but some targeting both xanthine oxidoreductase and URAT1. Increasing the number of available medications will ensure proper control of hyperuricemia to target serum urate levels in the near future for most, if not all, patients with hyperuricemia.

Topics: Acetamides; Drug Design; Gout; Gout Suppressants; Humans; Hyperuricemia; Imino Furanoses; Molecular Targeted Therapy; Phenylacetates; Pyrimidinones; Thioglycolates; Triazoles; Uricosuric Agents

Over the past decade much has been learned about the mechanisms of crystal-induced inflammation and renal excretion of uric acid, which has led to more specific targeting of gout therapies and a more potent approach to future management of gout. This article outlines agents being developed for more aggressive lowering of urate and more specific anti-inflammatory activity. The emerging urate-lowering therapies include lesinurad, arhalofenate, ulodesine, and levotofisopam. Novel gout-specific anti-inflammatories include the interleukin-1β inhibitors anakinra, canakinumab, and rilonacept, the melanocortins, and caspase inhibitors. The historic shortcomings of current gout treatment may, in part, be overcome by these novel approaches.

Topics: Acetamides; Adrenocorticotropic Hormone; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antirheumatic Agents; Benzodiazepines; Febuxostat; Gout; Gout Suppressants; Humans; Imino Furanoses; Interleukin 1 Receptor Antagonist Protein; Interleukin-1beta; Melanocortins; Phenylacetates; Polyethylene Glycols; Pyrimidinones; Recombinant Fusion Proteins; Thiazoles; Thioglycolates; Triazoles; Urate Oxidase; Uricosuric Agents

The uric acid metabolism pathway is more similar in primates and humans than in rodents. However, there are no reports of using primates to establish animal models of hyperuricaemia (HUA).. To establish an animal model highly related to HUA in humans.. Inosine (75, 100 and 200 mg/kg) was intraperitoneally administered to adult male rhesus monkeys (. Inosine (200 mg/kg) effectively increased the SUA level in rhesus monkeys from 51.77 ± 14.48 at 0 h to 178.32 ± 14.47 μmol/L within 30 min and to peak levels (201.41 ± 42.73 μmol/L) at 1 h. PNP mRNA level was increased, whereas XO mRNA and protein levels in the liver were decreased by the inosine group compared with those in the control group. No changes in mRNA and protein levels of the renal uric acid transporter were observed. Ulodesine, allopurinol and febuxostat eliminated the inosine-induced elevation in SUA in tested monkeys.. An acute HUA animal model with high reproducibility was induced; it can be applied to evaluate new anti-HUA drugs

Topics: Acute Disease; Allopurinol; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Febuxostat; Hyperuricemia; Imino Furanoses; Inosine; Macaca mulatta; Male; Pyrimidinones; Reproducibility of Results; Uric Acid

The CXCR4 receptor (Chemokine C-X-C motif receptor 4) is highly expressed in different hematological malignancies including chronic lymphocytic leukemia (CLL). The CXCR4 ligand (CXCL12) stimulates CXCR4 promoting cell survival and proliferation, and may contribute to the tropism of leukemia cells towards lymphoid tissues. Therefore, strategies targeting CXCR4 may constitute an effective therapeutic approach for CLL. To address that question, we studied the effect of Ulocuplumab (BMS-936564), a fully human IgG4 anti-CXCR4 antibody, using a stroma--CLL cells co-culture model. We found that Ulocuplumab (BMS-936564) inhibited CXCL12 mediated CXCR4 activation-migration of CLL cells at nanomolar concentrations. This effect was comparable to AMD3100 (Plerixafor--Mozobil), a small molecule CXCR4 inhibitor. However, Ulocuplumab (BMS-936564) but not AMD3100 induced apoptosis in CLL at nanomolar concentrations in the presence or absence of stromal cell support. This pro-apoptotic effect was independent of CLL high-risk prognostic markers, was associated with production of reactive oxygen species and did not require caspase activation. Overall, these findings are evidence that Ulocuplumab (BMS-936564) has biological activity in CLL, highlight the relevance of the CXCR4-CXCL12 pathway as a therapeutic target in CLL, and provide biological rationale for ongoing clinical trials in CLL and other hematological malignancies.

Topics: Actins; Antineoplastic Agents; Apoptosis; Benzylamines; Cell Movement; Cell Proliferation; Cell Survival; Chemokine CXCL12; Cyclams; Enzyme Activation; Heterocyclic Compounds; Humans; Imino Furanoses; Jurkat Cells; Leukemia, Lymphocytic, Chronic, B-Cell; Leukocytes, Mononuclear; Pyrimidinones; Reactive Oxygen Species; Receptors, CXCR4; Tumor Cells, Cultured; Tumor Suppressor Protein p53