pyrimidinones and Hyperuricemia

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

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

Lesch-Nyhan disease (LND) is a rare X-linked genetic disorder, with complete hypoxanthine-guanine phosphoribosyltransferase (HGPRT) deficiency, uric acid (UA), hypoxanthine and xanthine accumulation, and a devastating neurologic syndrome. UA excess, causing renal failure, is commonly decreased by xanthine oxidoreductase (XOR) inhibitors, such as allopurinol, yielding a xanthine and hypoxanthine increase. Xanthine accumulation may result in renal stones, while hypoxanthine excess seems involved in the neurological disorder. Inhibition of purine nucleoside phosphorylase (PNP) represents a different strategy for lowering urate. PNP catalyzes the cleavage of purine ribo- and d-ribo-nucleosides into ribose/deoxyribose phosphate and free bases, starting catabolism to uric acid. Clinical trials demonstrated that PNP inhibitors, initially developed as anticancer drugs, lowered UA in some gouty patients, in association or not with allopurinol. The present study tested the reliability of an analogue of immucillin-G (C1a), a PNP inhibitor, as a therapy for urate, hypoxanthine, and xanthine excess in LND patients by blocking hypoxanthine production upstream. The therapeutic aim is to limit the administration of XOR inhibitors to LND patients by supplying the PNP inhibitor in low doses, avoiding d-nucleoside toxicity. We report studies conducted in primary cultures of skin fibroblasts from controls and LND patients grown in the presence of the PNP inhibitor. Cell viability, oxypurine release in culture medium, and endocellular nucleotide pattern have been monitored in different growth conditions (inhibitor concentration, time, added inosine). Our results demonstrate effective PNP inhibition by low inhibitor concentration, with reduced hypoxanthine release, and no appreciable toxicity in control or patient cells, suggesting a new therapeutic strategy for LND hyperuricemia.

Topics: Allopurinol; Cells, Cultured; Enzyme Inhibitors; Humans; Hyperuricemia; Hypoxanthine; Hypoxanthine Phosphoribosyltransferase; Lesch-Nyhan Syndrome; Purine-Nucleoside Phosphorylase; Purines; Pyrimidinones; Pyrroles; Reproducibility of Results; Uric Acid; Xanthine

The identification of novel, non-purine based inhibitors of xanthine oxidase is described. After a high-throughput screening campaign, an NMR based counterscreen was used to distinguish actives, which interact with XO in a reversible manner, from assay artefacts. This approach identified pyrimidone 1 as a reversible and competitive inhibitor with good lead-like properties. A hit to lead campaign gave compound 41, a nanomolar inhibitor of hXO with efficacy in the hyperuricemic rat model after oral dosing.

Topics: Animals; Binding Sites; Drug Evaluation, Preclinical; Enzyme Activation; Enzyme Inhibitors; Gout Suppressants; Half-Life; High-Throughput Screening Assays; Hyperuricemia; Magnetic Resonance Spectroscopy; Molecular Docking Simulation; Protein Binding; Protein Structure, Tertiary; Pyrimidinones; Rats; Structure-Activity Relationship; Xanthine Oxidase