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Activation of PKG1α is a compelling strategy for the treatment of cardiovascular diseases. As the main effector of cyclic guanosine monophosphate (cGMP), activation of PKG1α induces smooth muscle relaxation in blood vessels, lowers pulmonary blood pressure, prevents platelet aggregation, and protects against cardiac stress. The development of activators has been mostly limited to cGMP mimetics and synthetic peptides. Described herein is the optimization of a piperidine series of small molecules to yield activators that demonstrate

We provide an account of synthetic strategies aimed at the efficient preparation of 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (3), an important cyclic sulfone building block for medicinal chemistry. A practical and scalable protocol has been developed that readily gives access to the title compound from commercially available and inexpensive starting materials. In addition, this novel approach has enabled the synthesis of various related 4,4-disubstituted cyclic sulfone derivatives that serve as valuable structural motifs for drug discovery.

이 연구는 갈등 이슈가 소셜 웹(Social Web)에서 어떻게 나타났는지를 분석했다. 정부가 구축한 빅데이터 공통기반 플랫폼 ‘혜안’을 활용해 대전시의 도시철도 2호선 ‘트램’의 정책결정과정에서 나타난 주요 이슈들을 소셜분석했다. ‘트램’을 키워드로 4년간의 뉴스 및 블로그․트위터를 4개의 시기로 나눠 분석한 결과 뉴스가 80%이상을 차지했지만 트램을 결정한 1시기에는 새로운 교통수단에 대한 시민들의 관심과 찬반 논쟁이 트위터(55.2%)에서 뜨거웠다. 주요 키워드로 검색된 ‘노면전차’, ‘교통약자’, ‘정치자금법 위반 혐의’, ‘시장직’, ‘시민들’, ‘예타면제’ 같은 단어들은 각 시기별 특성을 반영했다. 정책을 결정(1시기)한 자치단체장이 정치자금법 위반 혐의로 시장직을 상실(2시기)한 시기에는 ‘문제’, ‘논란’, ‘어렵’, ‘우려’와 같은 부정키워드들이 주를 이뤘다. 특히 뉴스 검색에서는 기자회견이나 성명서 등 보도자료 중심의 기사가 대부분이어서 언론의 심층 기획보도가 부족함을 드러냈다. 이 연구를 통해 지방자치단체가 범정부 빅데이터 시스템인 ‘혜안’을 통해 정책을 개발하고 민의(民意)를 파악함으로써 사회적 갈등 관리에 활용할 수 있다는 것을 알게 되었다. 또한 갈등 이슈에 대한 언론의 적극적인 취재보도의 필요성도 확인했다.

Increasing the efficiency of the drug discovery process is a challenge faced by drug hunters everywhere. One strategy medicinal chemists employ to meet this challenge is learning from knowledge sources within and beyond their organization. In this Perspective, we discuss the evolution of mechanisms for medicinal chemistry knowledge capture and sharing at MerckCo. over the past 15 years. We describe our approach to knowledge management and report on the multiple enduring and complementary teams and initiatives we have created to capture and share knowledge within a geographically diverse medicinal chemistry community. In addition, this Perspective will share the benefits we have observed and also reflect on what has allowed our efforts to be both successful and sustainable.

Background Although unusually high levels of blood mercury have been reported in the North Gyeongsang Province (Gyeongsangbuk-do), mercury contents from shark meat distributed in this region have not been assessed yet. Thus, this study aims to identify the hazard by evaluating the mercury contents of the shark meat sold in the traditional market of Gyeongsangbuk-do. Methods The shark meat in the form of muscle meat was obtained from 15 traditional markets of Gyeongsangbuk-do in the summer and winter of 2013. Out of 105 samples in total, 49 were collected in the summer and 56 in the winter. The total mercury concentration was measured by the combustion-gold amalgamation method using an automatic mercury analyzer (Milestone DMA-80, Milestone). Results The average mercury concentration of shark meat was 2.29 ± 1.77 µg/g, ranging between 0.06-8.93 µg/g with a geometric mean of 1.44 µg/g, which is higher than those reported in many countries. The mercury concentration in 77 of 105 shark meat samples exceeded 1 µg/g. Mercury concentration ranged between 0.09-8.93 µg/g (geometric mean: 1.45) in the summer and 0.06-6.73 µg/g (geometric mean: 1.48) in the winter. Conclusions Shark meat sold in the market contained a substantial amount of mercury. This suggests that it is difficult to reduce mercury intake by simply strengthening the standard level of mercury concentration in shark meat. Therefore, it is need to communication and awareness programs with consumers about hazardous effects of mercury inherent in shark meat.

본 연구는 종합병원에 근무하는 간호사를 대상으로 이들의 건강수준(SF-36)을 파악하고, 건강수준과 인구사회학적 특성, 직업관련 특성 및 직무스트레스 내용 등의 제 요인들과의 관련성을 파악하고자 실시하였다. 조사대상은 250병상 이상의 6개 종합병원에 근무하고 있는 간호사 572명으로 하였으며, 자료 수집은 2014년 5월 1일부터 5월 31일까지의 기간 동안에 구조화된 무기명 자기기입식 설문지를 이용한 설문조사에 의하였다. 연구결과, 조사대상 간호사들의 건강수준(SF-36)은 개인의 인구사회학적 특성, 건강관련행위 특성 및 직업관련 특성뿐만 아니라 직무스트레스 내용과도 유의한 관련성이 있음을 시사하고 있다. 특히 건강수준(SF-36)은 직무스트레스 내용에 있어서 업무 요구도가 낮고, 업무의 자율성, 상사 및 동료의 지지도가 높을 때 높아지는 것을 알 수 있다. 따라서 간호사의 직무스트레스를 통제할 수 있는 조직 내 시스템 개발과 분위기 조성이 우선되어져야 할 것이며, 또한, 간호사들의 건강수준(SF-36)을 증대시키기 위한 프로그램 개발이 필요하다고 사료된다. 【This research has been conducted to understand relations in general hospital nurses health level (SF-36), sociodemographic characteristics, health related factors, job related factors, and job stress. The subjects of the research are 572 nurses who are working in six different general hospitals with 250 beds. Data which has been collected from self administered questionnaire during the period from May 1st, 2014 to may 31th. The result has described, the health level(SF-36) of nurses has strong relation to sociodemographic characteristics, health related factors, job related factors, and even job stress. Especially the health level (SF-36) of nurses has risen when the nurses have less job stress, lower job pressure and more support from supervisor and coworkers. Therefore, the primary things to create are system development and atmosphere which controls the nurses' job stresses. Moreover, it is also important to develop programs for nurses' career satisfaction.】

A novel class of 13 and 16 membered steroidal macrocycles were synthesized by using ring closing metathesis reaction from the readily available anti-inflammatory steroids such as prednisolone, 6-methyl prednisolone, and 16-methyl prednisolone.

The effect of silicone softeners on hair conditioning was investigated with varied silicone treatment conditions and different thermal stress conditions. When silicon (-Si-) content was quantified from the silicone-treated hair specimens, greater contents of -Si- were observed from the hair treated with silicone softeners having amino-functionality than from that treated with polydimethylsiloxane. The adsorption of amino silicone was enhanced at higher temperature and longer treatment duration. The amino silicone softeners adsorbed more effectively on hair surface especially at lowered concentrations. Combing force of hair was lowered in greater extent when the hair specimens were treated with amino silicone softeners than with polydimethylsiloxane. The luster of hair specimens which were repeatedly treated with amino silicone softeners, however, was lowered due to more diffusion of light by the adsorption of amino silicone softeners.

The protein arginine methyltransferase (PRMT) family of enzymes catalyzes the transfer of methyl groups from S-adenosylmethionine to the guanidino nitrogen atom of peptidylarginine to form monomethylarginine or dimethylarginine. We created several less polar analogues of the specific PRMT inhibitor AMI-1, and one such compound was found to have improved PRMT inhibitory activity over the parent molecule. The newly identified PRMT inhibitor modulated T helper cell function and thus may serve as a lead for further inhibitors useful for immune-mediated disease treatment.

Intramolecular [2+3] cycloaddition reaction of trimethylenemethane diyls that were generated successfully from the reaction of malonate anions containing diene units with propynyl iodonium salts via alkylidene carbene intermediates produced linearly fused triquinanes.

Molecular modeling was performed on a triazolo quinazoline lead compound to help develop a series of adenosine A2A receptor antagonists with improved hERG profile. Superposition of the lead compound onto MK-499, a benchmark hERG inhibitor, combined with pKa calculations and measurement, identified terminal fluorobenzene to be responsible for hERG activity. Docking of the lead compound into an A2A crystal structure suggested that this group is located at a flexible, spacious, and solvent-exposed opening of the binding pocket, making it possible to tolerate various functional groups. Transformation analysis (MMP, matched molecular pair) of in-house available experimental data on hERG provided suggestions for modifications in order to mitigate this liability. This led to the synthesis of a series of compounds with significantly reduced hERG activity. The strategy used in the modeling work can be applied to other medicinal chemistry programs to help improve hERG profile.

[reaction: see text] A tandem electrocyclic closure, perceived as the key step in a biomimetic approach to SNF 4435C and D, was tested with 1,1,8-trisubstituted tetraene substrates. The ratio of endo:exo products could be controlled by the choice of the RZ substituent at C-1. On the basis of these results, a short stereoselective route to an advanced SNF 4435 intermediate was devised.

The adenosine A2A receptor is a G-protein-coupled receptor (GPCR) that has been extensively studied during the past few decades because it offers numerous possibilities for therapeutic applications. Herein we describe adenosine A2A receptor distribution, signaling pathways, pharmacology, and molecular structure, followed by a summary and SAR discussion of the most relevant series of adenosine A2A agonists and antagonists. This review also provides an update of the A2A ligands that are undergoing or have undergone clinical studies, including the two currently marketed agonists adenosine and regadenoson.

The introduction of A ring pyrazole modification to the hydrocortisone C-21 heteroaryl thioethers generated compounds with excellent transrepression potency (IL-8 inhibition) compared to their hydrocortisone analogs. However, the transcriptional transactivation activity of these compounds were considerably higher than the corresponding hydrocortisone analogs. Among all the compounds evaluated, a quinoxaline thioether modification demonstrated the best overall in vitro separation.

The combination of highly efficient polymerizations with modular “click” coupling reactions has enabled the synthesis of wide variety of novel nanoscopic structures. Here we demonstrate the facile synthesis of a new class of clickable, branched nanostructures, polyethylene glycol (PEG)-branch-azide bivalent-brush polymers, facilitated by “graft-through” ring-opening metathesis polymerization (ROMP) of a branched norbornene-PEG-chloride macromonomer followed by halide-azide exchange. The resulting bivalent-brush polymers possess azide groups at the core near a polynorbornene backbone with PEG chains extended into solution; the structure resembles a unimolecular micelle. We demonstrate copper-catalyzed azide-alkyne cycloaddition (CuAAC) “click-to” coupling of a photocleavable doxorubicin (DOX)-alkyne derivative to the azide core. The CuAAC coupling was quantitative across a wide range of nanoscopic sizes (~6 – ~50 nm); UV photolysis of the resulting DOX-loaded materials yielded free DOX that was therapeutically effective against human cancer cells.

Intramolecular [2+3] cycloaddition reaction of trimethylenemethane diyls that were generated successfully from the reaction of malonate anions containing diene units with propynyl iodonium salts via alkylidene carbene intermediates produced linearly fused triquinanes.

Tris(2-benzimidazolylmethyl)amines have been found to be superior accelerating ligands for the copper(I)-catalyzed azide−alkyne cycloaddition reaction. Candidates bearing different benzimidazole N-substituents as well as benzothiazole and pyridyl ligand arms were evaluated by absolute rate measurements under relatively dilute conditions by aliquot quenching kinetics and by relative rate measurements under concentrated conditions by reaction calorimetry. Benzimidazole-based ligands with pendant alkylcarboxylate arms proved to be advantageous in the latter case. The catalyst system was shown to involve more than one active species, providing a complex response to changes in pH and buffer salts and the persistence of high catalytic rate in the presence of high concentrations of coordinating ligands. The water-soluble ligand (BimC4A)3 was found to be especially convenient for the rapid and high-yielding synthesis of several functionalized triazoles with 0.01−0.5 mol % Cu.

[reaction: see text] Halogenation of achiral trans-2-pyridone photodimers results in 1,3-migration of an amide nitrogen and formation of a chiral structure with six stereogenic centers and well-differentiated functionality. The reactivity of this product toward nucleophiles, including the allylic halide, is dominated by participation by the amide nitrogen.

The size and positioning of substituents on a tetraene, along with the Woodward−Hoffmann rules, control the relative stereochemistry at the four adjacent chiral centers that are generated in the 8π/6π electrocyclization cascade. A biomimetic synthesis of (−)-SNF4435 C and (+)-SNF4435 D exploits these steric effects and allows confirmation of the predicted absolute stereochemistry of the natural products.

The size and positioning of substituents on a tetraene, along with the Woodward-Hoffmann rules, control the relative stereochemistry at the four adjacent chiral centers that are generated in the 8pi/6pi electrocyclization cascade. A biomimetic synthesis of (-)-SNF4435 C and (+)-SNF4435 D exploits these steric effects and allows confirmation of the predicted absolute stereochemistry of the natural products.

[reaction: see text] A tandem electrocyclic closure, perceived as the key step in a biomimetic approach to SNF 4435C and D, was tested with 1,1,8-trisubstituted tetraene substrates. The ratio of endo:exo products could be controlled by the choice of the RZ substituent at C-1. On the basis of these results, a short stereoselective route to an advanced SNF 4435 intermediate was devised.

A bicyclo[3.1.0]hexane, with one cyclopropane carbon flanked by a ketone and an ester or an aldehyde, undergoes methanolysis with cleavage of one of the two activated cyclopropane bonds, depending on the reaction conditions. Acidic conditions yield primarily or exclusively a 4-methoxycyclohexane, while basic conditions yield a 3-methoxymethylcyclopentanone.

[reaction: see text] Photocycloaddition of 2-pyridones yields a rigid polycyclic product containing a 1,5-cyclooctadiene. The cis isomer, with the alkenes in close proximity, undergoes a transannular reaction when treated with chlorine to give a polyquinane product. The chlorination reaction involves migration of an amide nitrogen and forms a single isomer, generating eight stereogenic centers in two steps.