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Mutations in β-cardiac myosin, the predominant motor protein for human heart contraction, can alter power output and cause cardiomyopathy. However, measurements of the intrinsic force, velocity, and ATPase activity of myosin have not provided a consistent mechanism to link mutations to muscle pathology. An alternative model posits that mutations in myosin affect the stability of a sequestered, super relaxed state (SRX) of the protein with very slow ATP hydrolysis and thereby change the number of myosin heads accessible to actin. Here we show that purified human β-cardiac myosin exists partly in an SRX and may in part correspond to a folded-back conformation of myosin heads observed in muscle fibers around the thick filament backbone. Mutations that cause hypertrophic cardiomyopathy destabilize this state, while the small molecule mavacamten promotes it. These findings provide a biochemical and structural link between the genetics and physiology of cardiomyopathy with implications for therapeutic strategies.

\"Udenafil\" is a phosphodiesterase-5 inhibitor indicated for erectile dysfunction. \"Dapoxetine\" is a serotonin transport inhibitor indicated for premature ejaculation. The aim of the study reported here was to investigate the pharmacokinetic drug interaction between udenafil and dapoxetine in healthy male subjects. An open-label, three-treatment, six-sequence, three-period crossover study was performed in healthy male subjects. In varying sequences, each subjects received single oral doses of udenafil 200 mg, dapoxetine 60 mg, and both treatments. The periods were separated by a washout period of 7 days. Serial blood samples were collected up to 48 hours after dosing. The plasma concentrations of udenafil and dapoxetine were determined using a validated liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were obtained by non-compartmental analysis. Tolerability was assessed throughout the study. Twenty-three healthy subjects completed the study. The geometric mean ratios of the area under the plasma concentration-time curve from time 0 to last measurable time point and measured peak plasma concentration for udenafil were 0.923 (90% confidence interval [CI]: 0.863-0.987) and 0.864 (90% CI: 0.789-0.947), respectively. The geometric mean ratios of the area under the plasma concentration-time curve from time 0 to last measurable time point and measured peak plasma concentration for dapoxetine were 1.125 (90% CI: 1.044-1.213) and 0.837 (90% CI: 0.758-0.925), respectively. There were no serious adverse events reported, and none of the subjects dropped out due to adverse events. Udenafil was found to have no clinically significant pharmacokinetic interactions with dapoxetine. The concurrent administration of udenafil and dapoxetine was generally well tolerated.

Hypertrophic cardiomyopathy (HCM) is an inherited disease of heart muscle that can be caused by mutations in sarcomere proteins. Clinical diagnosis depends on an abnormal thickening of the heart, but the earliest signs of disease are hyperdynamic contraction and impaired relaxation. Whereas some in vitro studies of power generation by mutant and wild-type sarcomere proteins are consistent with mutant sarcomeres exhibiting enhanced contractile power, others are not. We identified a small molecule, MYK-461, that reduces contractility by decreasing the adenosine triphosphatase activity of the cardiac myosin heavy chain. Here we demonstrate that early, chronic administration of MYK-461 suppresses the development of ventricular hypertrophy, cardiomyocyte disarray, and myocardial fibrosis and attenuates hypertrophic and profibrotic gene expression in mice harboring heterozygous human mutations in the myosin heavy chain. These data indicate that hyperdynamic contraction is essential for HCM pathobiology and that inhibitors of sarcomere contraction may be a valuable therapeutic approach for HCM.

Enantioselective carbon–hydrogen (C–H) activation reactions by asymmetric metallation could provide new routes for the construction of chiral molecules 1 , 2 . However, current methods are typically limited to the formation of five- or six-membered metallacycles, thereby preventing the asymmetric functionalization of C–H bonds at positions remote to existing functional groups. Here we report enantioselective remote C–H activation using a catalytic amount of a chiral norbornene as a transient mediator, which relays initial ortho -C–H activation to the meta position. This was used in the enantioselective meta -C–H arylation of benzylamines, as well as the arylation and alkylation of homobenzylamines. The enantioselectivities obtained using the chiral transient mediator are comparable across different classes of substrates containing either neutral σ-donor or anionic coordinating groups. This relay strategy could provide an alternative means to remote chiral induction, one of the most challenging problems in asymmetric catalysis 3 , 4 . Remote, enantioselective C–H activation reactions can be achieved by relaying ortho -C–H activation to the meta position, using a chiral norbornene as the mediator.

In anilines and benzylic amines, a recyclable chemical template can direct the olefination and acetoxylation of meta -C–H bonds as far as 11 bonds away from a functional group; in particular, it is able to direct the meta -selective C–H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. Site selective remote C–H bond activation To fully realize the synthetic potential of carbon–hydrogen (C–H) bond activation in organic chemistry, it is important to develop new approaches that can activate C–H bonds selectively in various locations with respect to existing functional groups. In this paper, Jin-Quan Yu and colleagues use a recyclable template to direct the olefination and acetoxylation of remote meta -C–H bonds — up to eleven bonds away — of anilines and benzylic amines. This template is able to direct the meta -selective C–H functionalization of tetrahydroquinoline, benzoxazines, anilines, benzylamines, 2-phenylpyrrolidines and 2-phenylpiperidines, all of which are commonly used building blocks in drug discovery. Achieving site selectivity in carbon–hydrogen (C–H) functionalization reactions is a long-standing challenge in organic chemistry. The small differences in intrinsic reactivity of C–H bonds in any given organic molecule can lead to the activation of undesired C–H bonds by a non-selective catalyst. One solution to this problem is to distinguish C–H bonds on the basis of their location in the molecule relative to a specific functional group. In this context, the activation of C–H bonds five or six bonds away from a functional group by cyclometallation has been extensively studied 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 . However, the directed activation of C–H bonds that are distal to (more than six bonds away) functional groups has remained challenging, especially when the target C–H bond is geometrically inaccessible to directed metallation owing to the ring strain encountered in cyclometallation 14 , 15 . Here we report a recyclable template that directs the olefination and acetoxylation of distal meta -C–H bonds—as far as 11 bonds away—of anilines and benzylic amines. This template is able to direct the meta -selective C–H functionalization of bicyclic heterocycles via a highly strained, tricyclic-cyclophane-like palladated intermediate. X-ray and nuclear magnetic resonance studies reveal that the conformational biases induced by a single fluorine substitution in the template can be enhanced by using a ligand to switch from ortho - to meta -selectivity.

Immunological complexity in atherosclerosis warrants targeted treatment of specific inflammatory cells that aggravate the disease. With the initiation of large phase III trials investigating immunomodulatory drugs for atherosclerosis, cardiovascular disease treatment enters a new era. We here propose a radically different approach: implementing and evaluating in vivo a combinatorial library of nanoparticles with distinct physiochemical properties and differential immune cell specificities. The library’s nanoparticles are based on endogenous high-density lipoprotein, which can preferentially deliver therapeutic compounds to pathological macrophages in atherosclerosis. Using the apolipoprotein E-deficient (Apoe −/−) mouse model of atherosclerosis, we quantitatively evaluated the library’s immune cell specificity by combining immunological techniques and in vivo positron emission tomography imaging. Based on this screen, we formulated a liver X receptor agonist (GW3965) and abolished its liver toxicity while still preserving its therapeutic function. Screening the immune cell specificity of nanoparticles can be used to develop tailored therapies for atherosclerosis and other inflammatory diseases.

The treatment for ischemic stroke is one of the most challenging problems and the therapeutic effect remains unsatisfied due to the poor permeation of drugs across the blood brain barrier (BBB). In this study, HAIYPRH (T7), a peptide that targeted to transferrin receptor (TfR) can mediate the transport of nanocarriers across the BBB, was conjugated to liposomes for ischemic stroke targeting treatment of a novel neuroprotectant (ZL006). T7-conjugated PEGylated liposomes (T7-P-LPs) loaded with ZL006 (T7-P-LPs/ZL006) were showed satisfactory vesicle size and size distribution. Furthermore, the cellular uptake results showed that T7 modification increased liposomes uptake by the brain capillary endothelial cells (BCECs) and little cytotoxicity of liposomes with or without ZL006 was observed. The in vivo biodistribution and near-infrared fluorescence imaging evidenced that T7 modification rendered liposomes significantly enhanced the transport of liposomes across the BBB. The pharmacodynamic study suggested that, T7-P-LPs/ZL006 exhibited reduced infarct volume and ameliorated neurological deficit compared with unmodified liposomes or free ZL006. T7-P-LPs/ZL006 could be targeted to brain and displayed remarkable neuroprotective effects. They could be used as a potential targeted drug delivery system of ischemic stroke treatment.

Biocatalysis contributes significantly to the development of more sustainable synthetic pathways by using mild reaction conditions and water as a solvent. However, many relevant classes of compounds, including privileged groups in drug design, are not yet accessible via enzymatic pathways. In this context, the development of an enzymatic route to indazoles remains an unmet challenge. Here, we present a nitroreductase-triggered indazole formation, in which 2-nitrobenzylamine derivatives are converted to reactive nitrosobenzylamine intermediates that spontaneously cyclize and aromatize to indazoles. Two nitroreductases accept a series of 2-nitrobenzylamine derivatives with excellent conversions (up to >99 %). In the case of N -substituted nitrosobenzylamines, 2 H -indazoles are formed, whereas other derivatives led to 1 H -indazoles. The synthetic value of the nitroreductase-triggered indazole formation is further demonstrated by successful coupling with an imine reductase in a sequential cascade reaction on a 50 mg scale. With this cascade, 2 H -indazoles are accessible from cheap 2-nitrobenzaldehyde and primary amines, resulting in up to 85 % conversion and 68 % isolated yield. An enzymatic route to indazoles, scaffolds present in many drugs, has not been developed yet. Here, the authors report nitroreductase-triggered indazole formation, in which 2-nitrobenzylamine derivatives are converted to reactive nitrosobenzylamine intermediates that spontaneously cyclize and aromatize to indazoles.

Flow chemistry is an attractive alternative to batch chemistry in cases in which improved safety and reaction efficiency can be achieved. This protocol describes the assembly of a continuous flow apparatus from readily available and affordable parts. The adoption of and opportunities in continuous flow synthesis ('flow chemistry') have increased significantly over the past several years. Continuous flow systems provide improved reaction safety and accelerated reaction kinetics, and have synthesised several active pharmaceutical ingredients in automated reconfigurable systems. Although continuous flow platforms are commercially available, systems constructed 'in-lab' provide researchers with a flexible, versatile, and cost-effective alternative. Herein, we describe the assembly and use of a modular continuous flow apparatus from readily available and affordable parts in as little as 30 min. Once assembled, the synthesis of a sulfonamide by reacting 4-chlorobenzenesulfonyl chloride with dibenzylamine in a single reactor coil with an in-line quench is presented. This example reaction offers the opportunity to learn several important skills including reactor construction, charging of a back-pressure regulator, assembly of stainless-steel syringes, assembly of a continuous flow system with multiple junctions, and yield determination. From our extensive experience of single-step and multistep continuous flow synthesis, we also describe solutions to commonly encountered technical problems such as precipitation of solids ('clogging') and reactor failure. Following this protocol, a nonspecialist can assemble a continuous flow system from reactor coils, syringes, pumps, in-line liquid–liquid separators, drying columns, back-pressure regulators, static mixers, and packed-bed reactors.

We present a traumatic fatality of a 19-year-old man who had ingested blotter paper containing 25I-NBOMe [2-(4-iodo-2,5-dimethoxyphenyl)-N-[(2-methoxyphenyl)methyl]ethanamine]. Postmortem specimens were analyzed by high performance liquid chromatography with tandem mass spectrometry (HPLC/MS/MS). Toxicology findings for fluids based upon blood or urine calibrators were as follows: peripheral blood, 405pg/mL; heart blood, 410pg/mL; urine, 2.86ng/mL; and vitreous humor, 99pg/mL. While findings based upon the method of standard additions were: gastric contents, 7.1μg total; bile, 10.9ng/g; brain, 2.54ng/g and liver, 7.2ng/g. To our knowledge the presented case is the first postmortem case of 25I-NBOMe intoxication documented by toxicological analysis of tissues and body fluids.