Synthesis and SAR of aminothiazole fused benzazepines as selective dopamine D2 partial agonists.

Dopamine (D(2)) partial agonists (D2PAs) have been regarded as a potential treatment for schizophrenia patients with expected better side effect profiles than currently marketed antipsychotics. Herein we report the synthesis and SAR of a series of aminothiazole fused benzazepines as selective D(2) partial agonists. These compounds have good selectivity, CNS drug-like properties and tunable D(2) partial agonism. One of the key compounds, 8h, has good in vitro/in vivo ADME characteristics, and is active in a rat amphetamine-induced locomotor activity model.

Elucidation of a novel bioactivation pathway of a 3,4-unsubstituted isoxazole in human liver microsomes: formation of a glutathione adduct of a cyanoacrolein derivative after isoxazole ring opening.

Studies on the biotransformation of isoxazole rings have shown that molecules containing a C3-substituted isoxazole or a 1,2-benzisoxazole can undergo a two-electron reductive ring cleavage to form an imine. In the absence of a C3 substituent, the isoxazole ring opens via deprotonation of the C3 proton followed by N-O bond cleavage to yield an α-cyanoenol analog. We report the identification of a novel bioactivation pathway of a 3,4-unsubstituted isoxazole in human liver microsomes. After the enzyme-catalyzed cleavage of the 3,4-unsubstituted isoxazole ring of N-((2-isopropyl-7-methyl-1-oxoisoindolin-5-yl)methyl)isoxazole-5-carboxamide (P) in human liver microsomes, the formed α-cyanoenol (M1) condenses with formaldehyde to generate an α,ß-unsaturated Michael acceptor intermediate (a cyanoacrolein derivative, VII), which further reacts with the cysteinyl thiol of glutathione to yield a GSH adduct of a cyanoacrolein derivative (M3). The same adduct also is formed when M1, generated in 0.1 N NaOH aqueous solution, reacts with formaldehyde and GSH. (13)C-labeled methanol was used to confirm that methanol from the drug stock solution was oxidized by liver microsomal enzymes to formaldehyde and the carbon atom from methanol was finally incorporated in the corresponding GSH adduct. The formation of isoxazole ring-opened products (M1 and M2) in human liver microsomes is NADPH-dependent. M1 and M2 were found in human liver microsomes preincubated with 1-aminobenzotriazole (1 mM) and NADPH (5 mM) at ∼ 10% of the levels found in the samples in the absence of 1-aminobenzotriazole, suggesting that this biotransformation pathway is primarily catalyzed by cytochrome P450. The formation of M3 also was inhibited by 1-aminobenzotriazole at a similar level.

Discovery of novel positive allosteric modulators of the metabotropic glutamate receptor 5 (mGlu5).

Novel in vitro mGlu(5) positive allosteric modulators with good potency, solubility, and low lipophilicity are described. Compounds were identified which did not rely on the phenylacetylene and carbonyl functionalities previously observed to be required for in vitro activity. Investigation of the allosteric binding requirements of a series of dihydroquinolinone analogs led to phenylacetylene azachromanone 4 (EC(50) 11.5 nM). Because of risks associated with potential metabolic and toxicological liabilities of the phenylacetylene, this moiety was successfully replaced with a phenoxymethyl group (27; EC(50) 156.3 nM). Derivation of a second-generation of mGlu(5) PAMs lacking a ketone carbonyl resulted in azaindoline (33), azabenzimidazole (36), and N-methyl 8-azaoxazine (39) phenylacetylenes. By scoping nitrogen substituents and phenylacetylene replacements in 39, we identified phenoxymethyl 8-azaoxazine 47 (EC(50) 50.1 nM) as a potent and soluble mGlu(5) PAM devoid of both undesirable phenylacetylene and carbonyl functionalities.

2,6-Disubstituted pyrazines and related analogs as NR2B site antagonists of the NMDA receptor with anti-depressant activity.

Herein we describe the discovery of compounds that are competitive antagonists of the CP101-606 binding site within the NR2B subtype of the NMDA receptor. The compounds identified do not possess phenolic functional groups such as those in ifenprodil and related analogs. Initial identification of hits in this series focused on a basic, secondary amine side chain which led to good potency, but also presented a hERG liability. Further modifications led to examples of non-basic replacements which demonstrated much less liability in this regard. Finally, one compound in the series, 6a, was tested in the mouse forced swim depression assay and found to show activity (s.c. 60 mg/kg).

Future Lyme disease risk in the south-eastern United States based on projected land cover.

Lyme disease is the most significant vector-borne disease in the United States, and its southward advance over several decades has been quantified. Previous research has examined the potential role of climate change on the disease's expansion, but no studies have considered the role of future land cover upon its distribution. This research examines Lyme disease risk in the south-eastern U.S. based on projected land cover developed under four Intergovernmental Panel on Climate Change Scenarios: A1B, A2, B1, and B2. Land cover types and edge indices significantly associated with Lyme disease in Virginia were incorporated into a spatial Poisson regression model to quantify potential land cover suitability for Lyme disease in the south-eastern U.S. under each scenario. Our results indicate an intensification of potential land cover suitability for Lyme disease under the A scenarios and a decrease of potential land cover suitability under the B scenarios. The decrease under the B scenarios is a critical result, indicating that Lyme disease risk can be decreased by making different land cover choices. Additionally, health officials can focus efforts in projected high incidence areas.

Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency.

Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization.

The evaluation of land consolidation policy in improving agricultural productivity in China.

China is presently undergoing rapid economic development and unprecedented urbanization. Concerns over food security have prompted the Chinese government to implement large-scale land consolidation projects. However, no formal evaluation has been conducted on such projects. Thus, effectiveness of land consolidation policy remains uncertain. We obtained detailed geo-spatial information for 5328 land consolidation projects implemented between 2006 and 2010, and used time-series MODIS NDVI (2006-2016) data to assess effectiveness of China's land consolidation policy in improving agricultural productivity. Our results show that the overall effectiveness of land consolidation in improving agricultural productivity is low, which lies in contrast to optimistic estimates based on regional statistical analysis and theoretical approaches. For projects (n = 560) implemented in 2006, about 29.5% showed significant (p < 0.05) increasing trends of MODIS NDVI after implementation of land consolidation. For 2007-2010, lower percentages (e.g., 25.9% in 2007 and 13.5% in 2010) of projects showed significant increasing trends. Furthermore, we found effectiveness of land consolidation projects displayed clear regional differences and driving factors are inconsistent with policy design. We anticipate our research to be a starting point for a more comprehensive evaluation involving longer time-series and higher spatial resolution data.

An Examination of the Demographic and Environmental Variables Correlated with Lyme Disease Emergence in Virginia.

Lyme disease is the United States' most significant vector-borne illness. Virginia, on the southern edge of the disease's currently expanding range, has experienced an increase in Lyme disease both spatially and temporally, with steadily increasing rates over the past decade and disease spread from the northern to the southwestern part of the state. This study used a Geographic Information System and a spatial Poisson regression model to examine correlations between demographic and land cover variables, and human Lyme disease from 2006 to 2010 in Virginia. Analysis indicated that herbaceous land cover is positively correlated with Lyme disease incidence rates. Areas with greater interspersion between herbaceous and forested land were also positively correlated with incidence rates. In addition, income and age were positively correlated with incidence rates. Levels of development, interspersion of herbaceous and developed land, and population density were negatively correlated with incidence rates. Abundance of forest fragments less than 2 hectares in area was not significantly correlated. Our results support some findings of previous studies on ecological variables and Lyme disease in endemic areas, but other results have not been found in previous studies, highlighting the potential contribution of new variables as Lyme disease continues to emerge southward.

Addition of Transiently-Generated Methyl o-Lithiobenzoate to Imines. An Isoindolone Annulation.

Addition of phenyllithium to a mixture of an imine, methyl o-iodobenzoate, and BF(3).etherate at -105 degrees C gives good to excellent yields of isoindolones. The transient formation of methyl o-lithiobenzoate is proposed, which is formed by a rapid lithium/iodide exchange reaction of the phenyllithium with methyl o-iodobenzoate in the presence of the imine. The transiently generated anions can then be captured by the BF(3)-activated imines to form the isoindolones in good to high yield. The reactions conditions are sufficiently mild, and selective, to permit functional groups such carbmethoxy and aryl bromide, which could otherwise react with the added PhLi, to be tolerated.

Spatial and temporal emergence pattern of Lyme disease in Virginia.

The emergence of infectious diseases over the past several decades has highlighted the need to better understand epidemics and prepare for the spread of diseases into new areas. As these diseases expand their geographic range, cases are recorded at different geographic locations over time, making the analysis and prediction of this expansion complicated. In this study, we analyze spatial patterns of the disease using a statistical smoothing analysis based on areal (census tract level) count data of Lyme disease cases in Virginia from 1998 to 2011. We also use space and space-time scan statistics to reveal the presence of clusters in the spatial and spatiotemporal distribution of Lyme disease. Our results confirm and quantify the continued emergence of Lyme disease to the south and west in states along the eastern coast of the United States. The results also highlight areas where education and surveillance needs are highest.

Improving lead generation success through integrated methods: transcending 'drug discovery by numbers'.

Key methodologies such as HTS and combinatorial chemistry have allowed pharmaceutical discovery to focus on identifying promising drug candidates through the use of statistics. Thus, amassing large data sets from large-scale screening campaigns of ever-increasing corporate compound collections was expected to deliver unprecedented success for the pharmaceutical industry. This feature review explores aspects of how the reliance on using numbers to drive discovery has gone awry. Building knowledge equity from the integration of multiple parallel screening assays, workstreams and data sources provides an alternative to driving discovery through statistics. Thus, a more rational approach to creating and inventing new leads and drug opportunities may be pursued.

Attitudes towards vaccination among chiropractic and naturopathic students.

We have investigated the attitudes towards vaccination of undergraduate chiropractic and naturopathic students in the two major complementary and alternative medicine colleges in Canada. While the majority of the students were not averse to vaccination, we found in both colleges that anti-vaccination attitudes were more prevalent in the later years of the programs. Reasons for this are discussed, and we provide suggestions for strategies to address the situation.

Attitudes toward vaccination: a survey of Canadian chiropractic students.

BACKGROUND: Although the Canadian Chiropractic Association and the Canadian Memorial Chiropractic College (CMCC) endorse vaccination, the prevalence of anti-vaccination attitudes among Canadian chiropractors is unknown. This study describes the prevalence of anti-vaccination attitudes among Canadian chiropractic students. METHODS: An 11-item questionnaire about attitudes toward vaccination was distributed to students enrolled at CMCC during the 1999/2000 academic year. The responses for the 11 items were then summed to arrive at a total score ranging from 0 (most negative attitude toward vaccination) to 22 (most positive attitude toward vaccination). Respondents' perceptions of sources of vaccine information were also investigated. RESULTS: Over 75% of the students (467 of 621) completed the questionnaire. Most students (53.3%) reported that in general they agreed with vaccination. This was especially true among first-year students (60.7%). However, among fourth year students, only 39.5% agreed with vaccination. The proportion of respondents who stated that they were against vaccination in general was 5 (4.5%) of 112 first-year students, 10 (8.3%) of 121 second-year students, 16 (13.9%) of 115 third-year students and 35 (29.4%) of 119 fourth-year students. The mean scores on the questionnaire were progressively lower with each higher year of study at the College. The mean survey scores for each year of study were first year, 15.9 (95% confidence interval [CI] 15.2-16.6); second year, 16.1 (95% CI 15.3-1 7.0); third year, 14.5 (95% CI 13.5-15.4); and fourth year, 12.8 (95% CI 11.7-13.9). The mean scores varied among year of study and were statistically significant using one-way ANOVA (p < 0.0001). Among students who relied primarily on informal sources of vaccine information, such as the chiropractic literature and informal talks at CMCC, anti-vaccination attitudes were more prevalent in later years. INTERPRETATION: Most CMCC students reported pro-vaccination attitudes, but there appeared to be an increase in anti-vaccination attitudes as students progressed through the CMCC program. This pattern was seen almost exclusively among students who relied primarily on informal sources of vaccine information rather than on core CMCC lectures or prior lectures at university.