Discovery and Structure-Activity Relationship of a Ryanodine Receptor 2 Inhibitor.

Ryanodine receptor 2 (RyR2) is a large Ca-release channel in the sarcoplasmic reticulum (SR) of cardiac muscle cells. It serves to release Ca from the SR into the cytosol to initiate muscle contraction. RyR2 overactivation is associated with arrhythmogenic cardiac disease, but few specific inhibitors have been reported so far.

Anti-Inflammatory Effects of a Novel Nuclear Factor-B Inhibitory Derivative Derived from Pyrazolo[3,4-]Pyrimidine in Three Inflammation Models.

Nuclear factor-B (NF-B) plays a central role in inflammatory responses, and its physiologic functions are essential for cell survival and proliferation. Currently, drugs targeting NF-B inhibition have not yet been applied in clinical practice. We investigated the physiologic effect of a novel NF-B inhibitory compound, 1-pyrazolo[3,4-]pyrimidin-4-amine derivative (INH #1), on three inflammatory animal models.

A potent and selective cis-amide inhibitor of ryanodine receptor 2 as a candidate for cardiac arrhythmia treatment.

Ryanodine receptor 2 (RyR2) is a Ca release channel mainly located on the sarcoplasmic reticulum (SR) membrane of heart muscle cells and regulates the concentration of Ca in the cytosol. RyR2 overactivation causes potentially lethal cardiac arrhythmias, but no specific inhibitor is yet available. Herein we developed the first highly potent and selective RyR2 inhibitor, TMDJ-035, containing 3,5-difluoro substituents on the A ring and a 4-fluoro substituent on the B ring, based on a comprehensive structure-activity relationship (SAR) study of tetrazole compound 1.

Screening for Novel Type 2 Ryanodine Receptor Inhibitors by Endoplasmic Reticulum Ca Monitoring.

Type 2 ryanodine receptor (RyR2) is a Ca release channel on the endoplasmic (ER)/sarcoplasmic reticulum that plays a central role in the excitation-contraction coupling in the heart. Hyperactivity of RyR2 has been linked to ventricular arrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia and heart failure, where spontaneous Ca release via hyperactivated RyR2 depolarizes diastolic membrane potential to induce triggered activity. In such cases, drugs that suppress RyR2 activity are expected to prevent the arrhythmias, but there is no clinically available RyR2 inhibitors at present.

Solvent-Dependent Conformational Switching of N-Methyl-N,N'-diarylsquaramide.

,'-Diarylsquaramide and ,'-dialkylsquaramide are conformationally stable linkers with extended (trans, trans) and folded (cis, cis) structures, respectively, independently of external conditions. Here, we show that -monomethylated ,'-diarylsquaramides generally take a (trans, cis) structure in the crystal but show a solvent-dependent conformational equilibrium in solution. In particular, the stable conformer of -methyl-,'-bis(1-naphthyl)squaramide () changes depending upon the solvent.