Oxidative metabolism of razuprotafib (AKB-9778), a sulfamic acid phosphatase inhibitor, in human microsomes and recombinant human CYP2C8 enzyme.

Razuprotafib, a sulphamic acid-containing phosphatase inhibitor, is shown to undergo enzymatic oxidation and methylation to form a major metabolite in monkey and human excreta with an value of 633.LC-MS/MS analysis of samples derived from incubations of razuprotafib with human liver microsomes and recombinant CYP2C8 enzyme has elucidated the metabolic pathway for formation of the thiol precursor to the S-methyl metabolite MS633 ( 633).Under conditions, the major pathway of razuprotafib metabolism involves extensive oxidation of the thiophene and phenyl rings.

The disposition of subcutaneous injected C-razuprotafib (C-AKB-9778), a sulphamic acid phosphatase inhibitor, in nonclinical species and human.

The disposition of radioactivity following subcutaneous C-razuprotafib, a Tie2 activator, was explored in multiple species.The absorption and clearance of razuprotafib and total radioactivity in human plasma are rapid and pharmacokinetics support razuprotafib as primary circulating component. Radioactivity is distributed greater to human plasma than whole blood (B:P = 0.

Selective Kv1.5 blockers: development of (R)-1-(methylsulfonylamino)-3-[2-(4-methoxyphenyl)ethyl]-4-(4-methoxyphenyl)-2-imidazolidinone (KVI-020/WYE-160020) as a potential treatment for atrial arrhythmia.

Atrial fibrillation is the most prevalent form of cardiac arrhythmia. Current treatments extend the atrial effective refractory period by nonselective blockade of cardiac ion channels. An alternative approach selectively targeting the Kv1.

Evolution of thiazolidine-based blockers of human Kv1.5 for the treatment of atrial arrhythmias.

Blockade of the Kv1.5 ion channel is a potentially atrial-selective avenue for the treatment of atrial fibrillation and atrial flutter. The development and biological evaluation of a series of thiazolidine-based blockers of Kv1.

Discovery and in vitro/in vivo studies of tetrazole derivatives as Kv1.5 blockers.

A novel class of tetrazole-derived Kv1.5 blockers is disclosed. In in vitro studies, several compounds had IC(50)s ranging from 180 to 550 nM.

Discovery and synthesis of tetrahydroindolone-derived carbamates as Kv1.5 blockers.

A novel class of tetrahydroindolone-derived carbamates has been discovered whose members are potent Kv1.5 blockers. The in vitro data show that compounds 6 and 29 are quite potent.

Discovery and synthesis of tetrahydroindolone derived semicarbazones as selective Kv1.5 blockers.

A novel class of tetrahydroindolone-derived semicarbazones has been discovered as potent Kv1.5 blockers. In in vitro studies, several compounds exhibited very good potency for blockade of Kv1.

Synthesis and evaluation of (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones as Kv1.5 channel blockers for the treatment of atrial fibrillation.

A series of novel (2-phenethyl-2H-1,2,3-triazol-4-yl)(phenyl)methanones were prepared and examined for utility as Kv1.5 channel blockers for the treatment of atrial fibrillation.