Discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridines as potent and selective SST5 agonists for the treatment of congenital hyperinsulinism.

SST5 receptor activation potently inhibits insulin secretion from pancreatic ß-cells, and an orally available nonpeptide selective SST5 agonist may be used to effectively manage the blood glucose levels of congenital HI patients to avoid severe hypoglycemia. Our medicinal chemistry efforts have led to the discovery of 4-(3-aminopyrrolidinyl)-3-aryl-5-(benzimidazol-2-yl)-pyridine analogs as potent SST5 agonists. This class of molecules exhibits excellent human SST5 potency and selectivity against SST1, SST2, SST3 and SST4 receptors. Leading compound 3-{4-[(3S)-3-aminopyrrolidin-1-yl]-5-(4-methyl-1H-1,3-benzodiazol-2-yl)pyridin-3-yl-5-fluorobenzonitrile (28, CRN02481) showed limited off-target activity and good pharmacokinetic profiles in both male Sprague Dawley rats and Beagle dogs to advance into further preclinical evaluations.

Three-Dimensional Mapping of Resistivity and Microstructure of Composite Electrodes for Lithium-Ion Batteries.

Nanoparticle silicon-graphite composite electrodes are a viable way to advance the cycle life and energy density of lithium-ion batteries. However, characterization of composite electrode architectures is complicated by the heterogeneous mixture of electrode components and nanoscale diameter of particles, which falls beneath the lateral and depth resolution of most laboratory-based instruments. In this work, we report an original laboratory-based scanning probe microscopy approach to investigate composite electrode microstructures with nanometer-scale resolution via contrast in the electronic properties of electrode components. Applying this technique to silicon-based composite anodes demonstrates that graphite, SiOx nanoparticles, carbon black, and LiPAA binder are all readily distinguished by their intrinsic electronic properties, with measured electronic resistivity closely matching their known material properties. Resolution is demonstrated by identification of individual nanoparticles as small as ∼20 nm. This technique presents future utility in multiscale characterization to better understand particle dispersion, localized lithiation, and degradation processes in composite electrodes for lithium-ion batteries.

Discovery of nonpeptide 3,4-dihydroquinazoline-4-carboxamides as potent and selective sst2 agonists.

Nonpeptide sst2 agonists can provide a new treatment option for patients with acromegaly, carcinoid tumors, and neuroendocrine tumors. Our medicinal chemistry efforts have led to the discovery of novel 3,4-dihydroquinazoline-4-carboxamides as sst2 agonists. This class of molecules exhibits excellent human sst2 potency and selectivity against sst1, sst3, sst4 and sst5 receptors. Leading compound 3-(3-chloro-5-methylphenyl)-6-(3-fluoro-2-hydroxyphenyl)-N,7-dimethyl-N-{[(2S)-pyrrolidin-2-yl]methyl}-3,4-dihydroquinazoline-4-carboxamide (28) showed no inhibition of major CYP450 enzymes (2C9, 2C19, 2D6 and 3A4) and weak inhibition of the hERG channel.

Embelin and its derivatives unravel the signaling, proinflammatory and antiatherogenic properties of GPR84 receptor.

GPR84 is an orphan G-protein coupled receptor, expressed on monocytes, macrophages and neutrophils and is significantly upregulated by inflammatory stimuli. The physiological role of GPR84 remains largely unknown. Medium chain fatty acids (MCFA) activate the receptor and have been proposed to be its endogenous ligands, although the high concentrations of MCFAs required for receptor activation generally exceed normal physiological levels. We identified the natural product embelin as a highly potent and selective surrogate GPR84 agonist (originally disclosed in patent application WO2007027661A2, 2007) and synthesized close structural analogs with widely varying receptor activities. These tools were used to perform a comprehensive study of GPR84 signaling and function in recombinant cells and in primary human macrophages and neutrophils. Activation of recombinant GPR84 by embelin in HEK293 cells results in Gi/o as well as G12/13-Rho signaling. In human macrophages, GPR84 initiates PTX sensitive Erk1/2 and Akt phosphorylation, PI-3 kinase activation, calcium flux, and release of prostaglandin E2. In addition, GPR84 signaling in macrophages elicits Gi Gßγ-mediated augmentation of intracellular cAMP, rather than the decrease expected from Giα engagement. GPR84 activation drives human neutrophil chemotaxis and primes them for amplification of oxidative burst induced by FMLP and C5A. Loss of GPR84 is associated with attenuated LPS-induced release of proinflammatory mediators IL-6, KC-GROα, VEGF, MIP-2 and NGAL from peritoneal exudates. While initiating numerous proinflammatory activities in macrophages and neutrophils, GPR84 also possesses GPR109A-like antiatherosclerotic properties in macrophages. Macrophage receptor activation leads to upregulation of cholesterol transporters ABCA1 and ABCG1 and stimulates reverse cholesterol transport. These data suggest that GPR84 may be a target of therapeutic value and that distinct modes of receptor modulation (inhibition vs. stimulation) may be required for inflammatory and atherosclerotic indications.

Degradation Mechanisms of Magnesium Metal Anodes in Electrolytes Based on (CF3SO2)2N- at High Current Densities.

The energy density of rechargeable batteries utilizing metals as anodes surpasses that of Li ion batteries, which employ carbon instead. Among possible metals, magnesium represents a potential alternative to the conventional choice, lithium, in terms of storage density, safety, stability, and cost. However, a major obstacle for metal-based batteries is the identification of electrolytes that show reversible deposition/dissolution of the metal anode and support reversible intercalation of ions into a cathode. Traditional Grignard-based Mg electrolytes are excellent with respect to the reversible deposition of Mg, but their limited anodic stability and compatibility with oxide cathodes hinder their applicability in Mg batteries with higher voltage. Non-Grignard electrolytes, which consist of ethereal solutions of magnesium(II) bis(trifluoromethanesulfonyl)imide (Mg(TFSI)2), remain fairly stable near the potential of Mg deposition. The slight reactivity of these electrolytes toward Mg metal can be remedied by the addition of surface-protecting agents, such as MgCl2. Hence, ethereal solutions of Mg(TFSI)2 salt with MgCl2 as an additive have been suggested as a representative non-Grignard Mg electrolyte. In this work, the degradation mechanisms of a Mg metal anode in the TFSI-based electrolyte were studied using a current density of 1 mA cm-2 and an areal capacity of ∼0.4 mAh cm-2, which is close to those used in practical applications. The degradation mechanisms identified include the corrosion of Mg metal, which causes the loss of electronic pathways and mechanical integrity, the nonuniform deposition of Mg, and the decomposition of TFSI- anions. This study not only represents an assessment of the behavior of Mg metal anodes at practical current density and areal capacity but also details the outcomes of interfacial passivation, which was detected by simple cyclic voltammetry experiments. This study also points out the absolute absence of any passivation at the electrode-electrolyte interface for the premise of developing electrolytes compatible with a metal anode.

Design and synthesis of new tricyclic indoles as potent modulators of the S1P1 receptor.

Modulators of S1P1 have proven utility for the treatment of autoimmune disease and efforts to identify new agents with improved safety and pharmacokinetic parameters are ongoing. Several new S1P1 chemotypes were designed and optimized for potency and oral bioavailability. These new agents are characterized by a 'tricyclic fused indole array' and are highly potent agonists of the S1P1 receptor.

Discovery of a novel trans-1,4-dioxycyclohexane GPR119 agonist series.

The design and optimization of a novel trans-1,4-dioxycyclohexane GPR119 agonist series is described. A lead compound 21 was found to be a potent and efficacious GPR119 agonist across species, and possessed overall favorable pharmaceutical properties. Compound 21 demonstrated robust acute and chronic regulatory effects on glycemic parameters in the diabetic or non-diabetic rodent models.

Discovery of 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamides as potent and selective CB2 receptor agonists.

The design and synthesis of novel 1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalen-4-carboxamide CB2 selective ligands for the potential treatment of pain is described. Compound (R,R)-25 has good balance between CB2 agonist potency and selectivity over CB1, and possesses overall favorable pharmaceutical properties. It also demonstrated robust in vivo efficacy mediated via CB2 activation in the rodent models of inflammatory and osteoarthritis pain after oral administration.

Discovery and optimization of 5-fluoro-4,6-dialkoxypyrimidine GPR119 agonists.

A series of 5-fluoro-4,6-dialkoxypyrimidine GPR119 modulators were discovered and optimized for in vitro agonist activity. A lead molecule was identified that has improved agonist efficacy relative to our clinical compound (APD597) and possesses reduced CYP2C9 inhibitory potential. This optimized lead was found to be efficacious in rodent models of glucose control both alone and in combination with a Dipeptidyl peptidase-4 (DPP-4) inhibitor.

Discovery of CRN04894: A Novel Potent Selective MC2R Antagonist.

A novel class of nonpeptide melanocortin type 2 receptor (MC2R) antagonists was discovered through modification of known nonpeptide MC4R ligands. Structure-activity relationship (SAR) studies led to the discovery of 17h (CRN04894), a highly potent and subtype-selective first-in-class MC2R antagonist, which demonstrated remarkable efficacy in a rat model of adrenocorticotrophic hormone (ACTH)-stimulated corticosterone secretion. Oral administration of 17h suppressed ACTH-stimulated corticosterone secretion in a dose-dependent manner at doses ≥3 mg/kg. With its satisfactory pharmaceutical properties, 17h was advanced to Phase 1 human clinical trials in healthy volunteers with the goal of moving into patient trials to evaluate CRN04894 for the treatment of ACTH-dependent diseases, including congenital adrenal hyperplasia (CAH) and Cushing's disease (CD).

Improvement of ß-cell function after achievement of optimal glycaemic control via long-term continuous subcutaneous insulin infusion therapy in non-newly diagnosed type 2 diabetic patients with suboptimal glycaemic control.

BACKGROUND: Achieving euglycaemia by continuous subcutaneous insulin infusion (CSII) therapy alone has been shown to restore ß-cell function in patients with newly diagnosed type 2 diabetes. However, the efficacy has not been evaluated in patients with non-newly diagnosed type 2 diabetes and suboptimal glycaemic control. METHODS: Of the 1220 patients with type 2 diabetes who began CSII therapy from March 2000 to March 2007, we retrospectively selected patients using the following inclusion criteria: glycosylated haemoglobin (HbA1c ) ≥ 7.0%, diabetes duration ≥ 1 year before CSII therapy, and duration of CSII therapy ≥ 6 months. We evaluated sequential changes in HbA1c and serum C-peptide levels measured at a 6- to 12-month intervals during CSII therapy. RESULTS: In the 521 subjects included in this study [median diabetes duration 10 years; interquartile range (IQR) 6.0-17.0; CSII therapy ≤ 30 months], median HbA1c decreased from 8.7% (IQR 7.7-10.0) at baseline to 6.3% (IQR 5.9-6.9) after 6 months of CSII therapy (p < 0.0001). During the subsequent 24 months, median HbA1c levels were maintained between 6.3% and 6.5% (p < 0.0001 for all time points vs baseline). At 12 months after CSII therapy, median C-peptide levels began to increase compared with baseline (fasting level 23% increase, p < 0.0001; 2-h postprandial level 26% increase, p = 0.022), and the increase was maintained at 30 months (fasting level 39%; 2-h postprandial level 53%; p < 0.0001 for all vs baseline). CONCLUSIONS: ß-Cell function was significantly improved in patients with non-newly diagnosed and suboptimally controlled type 2 diabetes after achieving and maintaining optimal glycaemic control with long-term CSII therapy alone.

A case of acute motor and sensory axonal neuropathy following hepatitis a infection.

Acute motor and sensory axonal neuropathy (AMSAN) are recently described subtypes of Guillain-Barre syndrome characterized by acute onset of distal weakness, loss of deep tendon reflexes, and sensory symptoms. A 21-yr-old male was transferred to our hospital due to respiration difficulties and progressive weakness. In laboratory findings, immunoglobulin M antibodies against hepatitis A were detected in blood and cerebrospinal fluid. The findings of motor nerve conduction studies showed markedly reduced amplitudes of compound muscle action potentials in bilateral peroneal, and posterior tibial nerves, without evidence of demyelination. Based on clinical features, laboratory findings, and electrophysiologic investigation, the patient was diagnosed the AMSAN following acute hepatitis A viral infection. The patient was treated with intravenous immunoglobulin and recovered slowly. Clinicians should consider this rare but a serious case of AMSAN following acute hepatitis A infection.

Structure Dependent Electrochemical Behaviors of Hard Carbon Anode Materials Derived from Natural Polymer for Next-Generation Sodium Ion Battery.

Hard carbons are one of the most promising anode materials for next-generation sodium-ion batteries due to their high reversible capacity, long cycle life, and low cost. The advantage in terms of price of hard carbons can be further improved by using cheaper resources such as biomass waste as precursors. Lignin is one of the richest natural bio-polymer in the earth which can be obtained from woods. As the lignin has three-dimensional amorphous polymeric structure, it is considered as good precursor for producing carbonaceous materials under proper carbonization processes for energy storage devices. In this study, structural properties of lignin-derived hard carbons such as interlayer spacing, degree of disorder and surface defects are controlled. Specifically, lignin-derived hard carbons were synthesized at 1000 °C, 1250 °C, and 1500 °C, and it was confirmed that the structure gradually changed from a disordered structure to ordered structure through X-ray diffraction, Raman spectroscopy, and X-ray photoelectron spectroscopy. Hard carbons exhibit sloping regions at high voltage and plateau region at low voltage during the electrochemical processes for sodium ions. As the heat treatment temperature increases, the contribution to the overall reversible capacity of the sloping region decreases and the contribution of the plateau region increases. This trend confirms that it affects reversible capacity, rate-capability, and cycling stability, meaning that an understanding of structural properties and related electrochemical properties is necessary when developing hard carbon as a negative electrode material for sodium ion batteries.

Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist.

The discovery of a novel 4-(4-aminopiperidinyl)-3,6-diarylquinoline series of potent SST2 agonists is described. This class of molecules exhibit excellent selectivity over SST1, SST3, SST4, and SST5 receptors. The compound 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile (22, paltusotine, formerly known as CRN00808) showed no direct inhibition of major cytochrome P450 enzymes or the hERG ion channel and had sufficient exposure in rats and excellent exposure in dogs upon oral dosing. In pharmacodynamic studies, compound 22 dose-dependently suppressed growth hormone (GH) secretion induced by an exogenous growth-hormone-releasing hormone (GHRH) challenge in both male and female rats following a single oral dose and suppressed IGF-1 levels with repeated oral administration in both rats and dogs. To the best of our knowledge, compound 22 is the first non-peptide SST2 agonist to advance to human clinical trials and is currently in Phase 3 trials in acromegaly patients and a Phase 2 trial in neuroendocrine tumor patients suffering from carcinoid syndrome.

Fused tricyclic indoles as S1P1 agonists with robust efficacy in animal models of autoimmune disease.

Two series of fused tricyclic indoles were identified as potent and selective S1P(1) agonists. In vivo these agonists produced a significant reduction in circulating lymphocytes which translated into robust efficacy in several rodent models of autoimmune disease. Importantly, these agonists were devoid of any activity at the S1P(3) receptor in vitro, and correspondingly did not produce S1P(3) mediated bradycardia in telemeterized rat.

A case of cerebellar infarction presenting as thunderclap headache.

Thunderclap headache (TCH) refers to a sudden-onset, severe headache that features in subarachnoid hemorrhage, unruptured intracranial aneurysm, cerebral venous thrombosis, pituitary apoplexy, cervical artery dissection, and hypertensive reversible posterior leukoencephalopathy. TCH is a rare manifestation in cerebral or cerebellar infarctions. Herein, we report on a 60-year-old woman with a thunderclap headache as the first symptom of cerebellar infarction, in the absence of abnormal findings in the brain computed tomography (CT), CT angiography, and lumbar puncture. An urgent brain MRI showed an acute infarction of the right cerebellar hemisphere. The next day, the patient presented with right side ataxia. In emergency cases presenting with thunderclap headache, one should consider an expanded evaluation and/or close observation, with frequent neurological examinations, even though the findings are normal on the initial neurological examination, cerebrospinal fluid analysis, and brain CT.

Promising therapeutics with natural bioactive compounds for improving learning and memory--a review of randomized trials.

Cognitive disorders can be associated with brain trauma, neurodegenerative disease or as a part of physiological aging. Aging in humans is generally associated with deterioration of cognitive performance and, in particular, learning and memory. Different therapeutic approaches are available to treat cognitive impairment during physiological aging and neurodegenerative or psychiatric disorders. Traditional herbal medicine and numerous plants, either directly as supplements or indirectly in the form of food, improve brain functions including memory and attention. More than a hundred herbal medicinal plants have been traditionally used for learning and memory improvement, but only a few have been tested in randomized clinical trials. Here, we will enumerate those medicinal plants that show positive effects on various cognitive functions in learning and memory clinical trials. Moreover, besides natural products that show promising effects in clinical trials, we briefly discuss medicinal plants that have promising experimental data or initial clinical data and might have potential to reach a clinical trial in the near future.

Electrochemical Sodiation Mechanism in Magnetite Nanoparticle-Based Anodes: Understanding of Nanoionics-Based Sodium Ion Storage Behavior of Fe3O4.

Electrochemical ion storage behaviors of Fe3O4 nanoparticles, as a representative transition metal oxide for an environmentally benign and low-cost anode for a sodium-ion battery, are thoroughly investigated through a combination of electrochemical analysis and diagnostics of Fe3O4 electrode cells, X-ray-based and spectroscopic analysis of material structure evolution as functions of depth of discharge (DoD) and state of charge (SoC), and first principle modeling. The gravimetric capacity is found to be 50 mA h/g for bulk Fe3O4 (50 nm average crystallite size) and 100 mA h/g─about a tenth of the theoretical prediction for complete conversion─for Fe3O4 nanoparticles (8.7 nm average particle size), respectively. A fundamental and mechanistic study of material evolution as functions of DoD and SoC shows that Fe3O4 does not allow electrochemical incorporation of Na+ ions into the empty cation positions of the inverse spinel structure, leading to our assertion that electrochemical intercalation of Na+ ions to conversion of the Fe3O4 anode in sodium-ion batteries is nonviable. A density functional theory investigation points to the impracticality of the intercalation of Na+ ions into Fe3O4 and further validates our experimental findings. We propose several possible mechanisms corresponding to the observed low capacity, including formation of solid electrolyte interphases with unfavorable properties and adsorption of Na+ ions onto surfaces of nanoparticles and/or at heterointerfaces in Fe3O4 composite electrodes in a NaPF6-based electrolyte system.

Discovery and characterization of potent and selective 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acids as S1P1 agonists.

S1P(1) receptor driven lymphopenia has proven utility in the treatment of an array of autoimmune disease states. As a part of our efforts to develop potent and selective S1P(1) receptor agonists, we have identified a novel chemical series of 4-oxo-4-(5-(5-phenyl-1,2,4-oxadiazol-3-yl)indolin-1-yl)butanoic acid S1P(1) receptor agonists.

Anti-neuroinflammatory activity of Kamebakaurin from Isodon japonicus via inhibition of c-Jun NH2-terminal kinase and p38 mitogen-activated protein kinase pathway in activated microglial cells.

Compelling evidence supports the notion that the majority of neurodegenerative diseases are associated with microglia-mediated neuroinflammation. Therefore, quelling of microglial activation may lead to neuronal cell survival. The present study investigated the effects of Kamebakaurin (KMBK), a kaurane diterpene isolated from Isodon japonicus HARA (Labiatae), on the production of pro-inflammatory mediators in lipopolysaccharide (LPS)-stimulated cytotoxicity in rat primary microglial cultures and the BV-2 cell line. KMBK significantly inhibited the LPS-induced production of nitric oxide (NO) in a concentration-dependent fashion in activated microglial cells. The mRNA and protein levels of inducible nitric oxide synthase (iNOS) and cyclooxycenase-2 (COX-2) were also decreased dose-dependently. Furthermore KMBK inhibited the JNK and p38 mitogen-activated protein kinases (MAPKs) in LPS-stimulated BV-2 microglial cells. Considering the results obtained, the present study authenticated the potential benefits of KMBK as a therapeutic target in ameliorating microglia-mediated neuroinflammatory diseases.