We designed a series of specifically deuterated benzopyran analogues as new COX-2 inhibitors with the aim of improving their pharmacokinetic properties. As expected, the deuterated compounds retained potency and selectivity for COX-2. The new molecules possess improved pharmacokinetic profiles in rats compared to their nondeuterated congeners. Most importantly, the new compounds showed pharmacodynamic efficacy in several murine models of inflammation and pain. The benzopyran derivatives were separated into their enantiomers, and the activity was found to reside with the S-isomers. To streamline the synthesis of the desired S-isomers, an organocatalytic asymmetric domino oxa-Michael/aldol condensation reaction was developed for their preparation. KEYWORDS: COX-2, coxib, deuterium, benzopyran, NSAID N onsteroidal anti-inflammatory drugs (NSAIDs) inhibit both COX-1 and COX-2 enzymes and have been a mainstay in clinical medicine for the treatment of inflammation and pain for many years. COX-2-selective inhibitors (coxibs) 1,2 developed in the mid 2000s supplanted traditional NSAIDs by virtue of their comparable efficacy with improved gastrointestinal safety. 3 Coxibs were initially thought to be able to avoid renal and cardiovascular side effects; however, this proved not to be entirely accurate. 4 In the kidney, COX-2 is expressed constitutively in certain regions (i.e., macula densa) and is highly regulated in response to changes in blood volume. COX-2-mediated metabolites (e.g., PGE 2 and PGI 2 ) play a mechanistic role in renin release, sodium excretion, and the maintenance of renal blood flow and glomerular filtration rate. 5 Coxibs fell into disfavor as clinical medicine because initial data linked them to cardiovascular risks of stroke and myocardial infarction compared with traditional NSAIDs. 6 However, data analysis from two recent clinical trials 7,8 clearly demonstrated that chronic and even short-term use of NSAIDs increased renal and cardiovascular side-effect risk no lesser than coxibs, and that the risks appeared to be drug-dependent rather than class-dependent. These data among other studies have inspired renewed interest in selective COX-2 inhibitors, particularly with coxibs that have a unique pharmacological profile, which could address unmet medical conditions. 9−12 Such clinical conditions include treating pain and inflammation without further compromising renal function and in treating or preventing certain types of cancer associated with inflammation mediated by COX-2.Benzopyran compounds as selective COX-2 inhibitors were investigated. 13−15 It was reported that 2-trifluoromethyl, 3-carboxy, and 4-H substituents were key elements of the benzopyran pharmacophore. Chiral chromatographic separation of 2-trifluoromethyl enantiomers and evaluation of the individual isomers showed that S-isomers were far more effective in blocking COX-2 activity than

Myotoxicity is a significant factor contributing to the poor adherence and reduced effectiveness in the treatment of statins. Genetic variations and high drug plasma exposure are considered as critique causes for statin-induced myopathy (SIM). This study aims to explore the sequential influences of rosuvastatin (RST) pharmacokinetic and myopathy-related single-nucleotide polymorphisms (SNPs) on the plasma exposure to RST and its metabolites: rosuvastatin lactone (RSTL) and N-desmethyl rosuvastatin (DM-RST), and further on RST-induced myopathy. A total of 758 Chinese patients with coronary artery disease were enrolled and followed up SIM incidents for 2 years. The plasma concentrations of RST and its metabolites were determined through a validated ultra-performance liquid chromatography mass spectrometry method. Nine SNPs in six genes were genotyped by using the Sequenom MassArray iPlex platform. Results revealed that ABCG2 rs2231142 variations were highly associated with the plasma concentrations of RST, RSTL, and DM-RST (P < 0.01, FDR < 0.05). CYP2C9 rs1057910 significantly affected the DM-RST concentration (P < 0.01, FDR < 0.05). SLCO1B1 rs4149056 variant allele was significantly associated with high SIM risk (OR: 1.741, 95% CI: 1.180-2.568, P = 0.0052, FDR = 0.0468). Glycine amidinotransferase (GATM) rs9806699 was marginally associated with SIM incidents (OR: 0.617, 95% CI: 0.406-0.939, P = 0.0240, FDR = 0.0960). The plasma concentrations of RST and its metabolites were not significantly different between the SIM (n = 51) and control groups (n = 707) (all P > 0.05). In conclusion, SLCO1B1 and GATM genetic variants are potential biomarkers for predicting RST-induced myopathy, and their effects on SIM are unrelated to the high plasma exposure of RST and its metabolites.

Drug-induced QT prolongation usually leads to torsade de pointes (TdP), thus for drugs in the early phase of development this risk should be evaluated. In the present study, we demonstrated a visualized transgenic zebrafish as an in vivo high-throughput model to assay the risk of drug-induced QT prolongation. Zebrafish larvae 48 h post-fertilization expressing green fluorescent protein in myocardium were incubated with compounds reported to induce QT prolongation or block the human ether-a-go-go-related gene (hERG) K⁺ current. The compounds sotalol, indapaminde, erythromycin, ofoxacin, levofloxacin, sparfloxacin and roxithromycin were additionally administrated by microinjection into the larvae yolk sac. The ventricle heart rate was recorded using the automatic monitoring system after incubation or microinjection. As a result, 14 out of 16 compounds inducing dog QT prolongation caused bradycardia in zebrafish. A similar result was observed with 21 out of 26 compounds which block hERG current. Among the 30 compounds which induced human QT prolongation, 25 caused bradycardia in this model. Thus, the risk of compounds causing bradycardia in this transgenic zebrafish correlated with that causing QT prolongation and hERG K⁺ current blockage in established models. The tendency that high logP values lead to high risk of QT prolongation in this model was indicated, and non-sensitivity of this model to antibacterial agents was revealed. These data suggest application of this transgenic zebrafish as a high-throughput model to screen QT prolongation-related cardio toxicity of the drug candidates.