Identification of Human UDP-Glucuronosyltransferase and Sulfotransferase as Responsible for the Metabolism of Dotinurad, a Novel Selective Urate Reabsorption Inhibitor.

Dotinurad, a novel selective urate reabsorption inhibitor, is used to treat hyperuricemia. In humans, orally administered dotinurad is excreted mainly as glucuronide and sulfate conjugates in urine. To identify the isoforms of UDP-glucuronosyltransferase (UGT) and sulfotransferase (SULT) involved in dotinurad glucuronidation and sulfation, microsome and cytosol fractions of liver, intestine, kidney, and lung tissues (cytosol only) were analyzed along with recombinant human UGT and SULT isoforms.

Ideal pharmacokinetic profile of dotinurad as a selective urate reabsorption inhibitor.

Dotinurad, a novel selective urate reabsorption inhibitor (SURI), has potent inhibitory effects at low doses on the uptake of urate by urate transporter 1 (URAT1, solute carrier family 22 member 12 [SLC22A12]), localized at the apical membrane of renal proximal tubular cells. This study sought to clarify the pharmacokinetic (PK) profile of dotinurad. In rats, monkeys, and humans, the apparent distribution volume (0.

Synthesis and σ receptor affinity of regioisomeric spirocyclic furopyridines.

In order to investigate systematically the effect of the position of the pyridine N-atom on the σ1 receptor affinity four regioisomeric furopyridines 2a-d were synthesized and pharmacologically evaluated. The key steps of the synthesis comprise bromine/lithium exchange at regioisomeric bromopyridinecarbaldehyde acetals 7a-d, subsequent addition to 1-benzylpiperidin-4-one and cyclization. The regioisomeric acetals 7a-d were obtained either by o-metalation of bromopyridines 5b and 5c or by oxidation of bromopicolines 3a and 3d.

Pyridine analogues of spirocyclic σ₁ receptor ligands.

Spirocyclic benzopyrans 2 interact with high affinity and selectivity with σ₁ receptors. Bioisosteric replacement of the benzene ring of the benzopyran substructure with the electron rich thiophene ring (3) led to increased σ₁ affinity. Herein the synthesis and pharmacological evaluation of electron deficient pyridine bioisosteres 4 are reported.

Metabolic profile of FYX-051 (4-(5-pyridin-4-yl-1h-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile) in the rat, dog, monkey, and human: identification of N-glucuronides and N-glucosides.

FYX-051, 4-(5-pyridin-4-yl-1H-[1,2,4]triazol-3-yl)pyridine-2-carbonitrile, is a novel xanthine oxidoreductase inhibitor that can be used for the treatment of gout and hyperuricemia. We examined the metabolism of FYX-051 in rats, dogs, monkeys, and human volunteers after the p.o.