Hyperoside inhibits proinflammatory cytokines in human lung epithelial cells infected with Mycoplasma pneumoniae.

Mycoplasma pneumoniae pneumonia (MPP) is the most common respiratory infection in young children and its incidence has increased worldwide. In this study, high expression of chemokine ligand 5 (CCL5) was observed in the serum of MPP patients, and its expression was positively correlated to DNA of M. pneumoniae (MP-DNA). In vitro, M. pneumoniae (MP) infection to A549 cells induced the expression of CCL5, chemokines receptor 4 (CCR4), nuclear factor-κB (NF-κB) nuclear protein, and phosphorylation of NF-κB-p65 (p-NF-κB-p65), whereas NF-κB cytoplasmic protein was decreased. On the contrary, treatment of hyperoside counteracted the induction of MP infection and promoted the proliferation of MP-infected A549 cells. Similarly, MP-induced IL-8 and TNF-α production was also markedly reduced by hyperoside. And CCR4 inhibitor AZD2098 had a better effect than hyperoside. In addition, CCL5 recombinant protein inhibited the effect of hyperoside to promote IL-8 and TNF-α production and CCR4 expression. These results indicated that CCL5 may be involved in the progression of MPP, and hyperoside was beneficial for MPP probably through CCL5-CCR4 interactions, which may provide a potential effective therapy for MPP.

Identification of a Potent, Highly Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor Clinical Candidate.

Computational modeling was used to direct the synthesis of analogs of previously reported phosphodiesterase 2A (PDE2A) inhibitor 1 with an imidazotriazine core to yield compounds of significantly enhanced potency. The analog PF-05180999 (30) was subsequently identified as a preclinical candidate targeting cognitive impairment associated with schizophrenia. Compound 30 demonstrated potent binding to PDE2A in brain tissue, dose responsive mouse brain cGMP increases, and reversal of N-methyl-d-aspartate (NMDA) antagonist-induced (MK-801, ketamine) effects in electrophysiology and working memory models in rats. Preclinical pharmacokinetics revealed unbound brain/unbound plasma levels approaching unity and good oral bioavailability resulting in an average concentration at steady state (Cav,ss) predicted human dose of 30 mg once daily (q.d.). Modeling of a modified release formulation suggested that 25 mg twice daily (b.i.d.) could maintain plasma levels of 30 at or above targeted efficacious plasma levels for 24 h, which became part of the human clinical plan.

Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor.

Phosphodiesterase 2A (PDE2A) inhibitors have been reported to demonstrate in vivo activity in preclinical models of cognition. To more fully explore the biology of PDE2A inhibition, we sought to identify potent PDE2A inhibitors with improved brain penetration as compared to current literature compounds. Applying estimated human dose calculations while simultaneously leveraging synthetically enabled chemistry and structure-based drug design has resulted in a highly potent, selective, brain penetrant compound 71 (PF-05085727) that effects in vivo biochemical changes commensurate with PDE2A inhibition along with behavioral and electrophysiological reversal of the effects of NMDA antagonists in rodents. This data supports the ability of PDE2A inhibitors to potentiate NMDA signaling and their further development for clinical cognition indications.

Regional assessment of CO2-solubility trapping potential: a case study of the coastal and offshore Texas Miocene interval.

This study presents a regional assessment of CO2-solubility trapping potential (CSTP) in the Texas coastal and offshore Miocene interval, comprising lower, middle, and upper Miocene sandstone. Duan's solubility model [Duan et al. Mar. Chem. 2006, 98, 131-139] was applied to estimate carbon content in brine saturated with CO2 at reservoir conditions. Three approaches (simple, coarse, and fine) were used to calculate the CSTP. The estimate of CSTP in the study area varies from 30 Gt to 167 Gt. Sensitivity analysis indicated that the CSTP in the study area is most sensitive to storage efficiency, porosity, and thickness and is least sensitive to background carbon content in brine. Comparison of CSTP in our study area with CSTP values for seven other saline aquifers reported in the literature showed that the theoretical estimate of CO2-solubility trapping potential (TECSTP) has a linear relationship with brine volume, regardless of brine salinity, temperature, and pressure. Although more validation is needed, this linear relationship may provide a quick estimate of CSTP in a saline aquifer. Results of laboratory experiments of brine-rock-CO2 interactions and the geochemical model suggest that, in the study area, enhancement of CSTP caused by interactions between brine and rocks is minor and the storage capacity of mineral trapping owing to mineral precipitation is relatively trivial.

Potential impacts of CO2 leakage on groundwater chemistry from laboratory batch experiments and field push-pull tests.

Storage of CO2 in deep saline reservoirs has been proposed to mitigate anthropogenically forced climate change. If injected CO2 unexpectedly migrates upward in shallow groundwater resources, potable groundwater may be negatively affected. This study examines the effects of an increase in pCO2 (partial pressure of CO2) on groundwater chemistry in a siliclastic-dominated aquifer by comparing a laboratory batch experiment and a field single-well push-pull test on the same aquifer sediment and groundwater. Although the aquifer mineralogy is predominately siliclastic, carbonate dissolution is the primary geochemical reaction. In the batch experiment, Ca concentrations increase until calcite saturation is reached at ~500 h. The concentrations of the elements Ca, Mg, Sr, Ba, Mn, and U are controlled by carbonate dissolution. Silicate dissolution controls Si and K concentrations and is ~2 orders of magnitude slower than carbonate dissolution. Changing pH conditions through the experiment initially mobilize Mo, V, Zn, Se, and Cd; sorption reactions later remove these elements from solution and concentrations drop to pre-experiment levels. The EPA's primary and secondary MCL's are not exceeded except for Mn, which exceeded the EPA's secondary standard of 0.05 mg/L. Push-pull results also identify carbonate and silicate dissolution reactions ~2 orders of magnitude slower than batch experiments.

Design and selection parameters to accelerate the discovery of novel central nervous system positron emission tomography (PET) ligands and their application in the development of a novel phosphodiesterase 2A PET ligand.

To accelerate the discovery of novel small molecule central nervous system (CNS) positron emission tomography (PET) ligands, we aimed to define a property space that would facilitate ligand design and prioritization, thereby providing a higher probability of success for novel PET ligand development. Toward this end, we built a database consisting of 62 PET ligands that have successfully reached the clinic and 15 radioligands that failed in late-stage development as negative controls. A systematic analysis of these ligands identified a set of preferred parameters for physicochemical properties, brain permeability, and nonspecific binding (NSB). These preferred parameters have subsequently been applied to several programs and have led to the successful development of novel PET ligands with reduced resources and timelines. This strategy is illustrated here by the discovery of the novel phosphodiesterase 2A (PDE2A) PET ligand 4-(3-[(18)F]fluoroazetidin-1-yl)-7-methyl-5-{1-methyl-5-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}imidazo[5,1-f][1,2,4]triazine, [(18)F]PF-05270430 (5).

Discovery, SAR, and pharmacokinetics of a novel 3-hydroxyquinolin-2(1H)-one series of potent D-amino acid oxidase (DAAO) inhibitors.

3-Hydroxyquinolin-2(1H)-one (2) was discovered by high throughput screening in a functional assay to be a potent inhibitor of human DAAO, and its binding affinity was confirmed in a Biacore assay. Cocrystallization of 2 with the human DAAO enzyme defined the binding site and guided the design of new analogues. The SAR, pharmacokinetics, brain exposure, and effects on cerebellum D-serine are described. Subsequent evaluation against the rat DAAO enzyme revealed a divergent SAR versus the human enzyme and may explain the high exposures of drug necessary to achieve significant changes in rat or mouse cerebellum D-serine.

3-Benzyl-1,3-oxazolidin-2-ones as mGluR2 positive allosteric modulators: Hit-to lead and lead optimization.

The discovery, synthesis and SAR of a novel series of 3-benzyl-1,3-oxazolidin-2-ones as positive allosteric modulators (PAMs) of mGluR2 is described. Expedient hit-to-lead work on a single HTS hit led to the identification of a ligand-efficient and structurally attractive series of mGluR2 PAMs. Human microsomal clearance and suboptimal physicochemical properties of the initial lead were improved to give potent, metabolically stable and orally available mGluR2 PAMs.