Synthesis and SAR of selective small molecule neuropeptide Y Y2 receptor antagonists

Highly potent and selective small molecule neuropeptide Y Y2 receptor antagonists are reported. The systematic SAR exploration of a hit molecule N-(4-ethoxyphenyl)-4-[hydroxy(diphenyl)methyl]piperidine-1-carbothioamide, identified from HTS, led to the discovery of highly potent NPY Y2 antagonists 16 (CYM 9484) and 54 (CYM 9552) with IC(50) values of 19 nM and 12 nM respectively.     

Maraviroc, a chemokine receptor-5 antagonist, fails to demonstrate efficacy in the treatment of patients with rheumatoid arthritis in a randomized, double-blind placebo-controlled trial

Introduction

The purpose of this study was to determine whether maraviroc, a human CC chemokine receptor 5 (CCR5) antagonist, is safe and effective in the treatment of active rheumatoid arthritis (RA) in patients on background methotrexate (MTX).

Methods

This phase IIa study comprised two distinct components: an open-label safety study of the pharmacokinetics (PK) of MTX in the presence of maraviroc, and a randomized, double-blind, placebo-controlled, proof-of-concept (POC) component. In the PK component, patients were randomized 1:1 to receive maraviroc 150 or 300 mg twice daily (BID) for four weeks. In the POC component, patients were randomized 2:1 to receive maraviroc 300 mg BID or placebo for 12 weeks. Patients were not eligible for inclusion in both components.

Results

Sixteen patients were treated in the safety/PK component. Maraviroc was well tolerated and there was no evidence of drug-drug interaction with MTX. One hundred ten patients were treated in the POC component. The study was terminated after the planned interim futility analysis due to lack of efficacy, at which time 59 patients (38 maraviroc; 21 placebo) had completed their week 12 visit. There was no significant difference in the number of ACR20 responders between the maraviroc (23.7%) and placebo (23.8%) groups (treatment difference -0.13%; 90% CI -20.45, 17.70; P = 0.504). The most common all-causality treatment-emergent adverse events in the maraviroc group were constipation (7.8%), nausea (5.2%), and fatigue (3.9%).

Conclusions

Maraviroc was generally well tolerated over 12 weeks; however, selective antagonism of CCR5 with maraviroc 300 mg BID failed to improve signs and symptoms in patients with active RA on background MTX.

Trial Registration

ClinicalTrials.gov: NCT00427934     

Prevalence of pulmonary tuberculosis - a baseline survey in central India

Background

The present study provides an estimate of the prevalence of bacteriologially positive pulmonary tuberculosis in Jabalpur, a district in central India.

Methodology/Principal Findings

A community based cross-sectional survey was undertaken in Jabalpur District of the central Indian state of Madhya Pradesh. A stratified cluster sampling design was adopted to select the sample. All eligible individuals were questioned for pulmonary symptoms suggestive of TB disease. Two sputum samples were collected from all eligible individuals and were examined by Ziehl-Neelsen smear microscopy and solid media culture methods. Of the 99,918 individuals eligible for screening, 95,071 (95.1%) individuals were screened. Of these, 7,916 (8.3%) were found to have symptoms and sputum was collected from 7,533 (95.2%) individuals. Overall prevalence of bacteriologically positive PTB was found to be 255.3 per 100,000 population (95% C.I: 195.3–315.4). Prevalence was significantly higher (p<0.001) amongst males (355.8; 95% C.I: 304.4–413.4) compared with females (109.0; 95% C.I: 81.2–143.3). Prevalence was also significantly higher in rural areas (348.9; 95% C.I: 292.6–412.8) as compared to the urban (153.9; 95% C.I: 123.2–190.1).

Conclusions/Significance

The TB situation in Jabalpur district, central India, is observed to be comparable to the TB situation at the national level (255.3 versus 249). There is however, a need to maintain and further strengthen TB control measures on a sustained and long term basis in the area to have a significant impact on the disease prevalence in the community.     

Exploration of natural compounds as sources of new bifunctional scaffolds targeting cholinesterases and beta amyloid aggregation: The case of chelerythrine

The presented project started by screening a library consisting of natural and natural based compounds for their acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity. Active compounds were chemically clustered into groups and further tested on the human cholinesterases isoforms. The aim of the presented study was to identify compounds that could be used as leads to target two key mechanisms associated with the AD’s pathogenesis simultaneously: cholinergic depletion and beta amyloid (Aβ) aggregation. Berberin, palmatine and chelerythrine, chemically clustered in the so-called isoquinoline group, showed promising cholinesterase inhibitory activity and were therefore further investigated. Moreover, the compounds demonstrated moderate to good inhibition of Aβ aggregation as well as the ability to disaggregate already preformed Aβ aggregates in an experimental set-up using HFIP as promotor of Aβ aggregates. Analysis of the kinetic mechanism of the AChE inhibition revealed chelerythrine as a mixed inhibitor. Using molecular docking studies, it was further proven that chelerythrine binds on both the catalytic site and the peripheral anionic site (PAS) of the AChE. In view of this, we went on to investigate its effect on inhibiting Aβ aggregation stimulated by AChE. Chelerythrine showed inhibition of fibril formation in the same range as propidium iodide. This approach enabled for the first time to identify a cholinesterase inhibitor of natural origin—chelerythrine—acting on AChE and BChE with a dual ability to inhibit Aβ aggregation as well as to disaggregate preformed Aβ aggregates. This compound could be an excellent starting point paving the way to develop more successful anti-AD drugs.     

Growth and photosynthetic pigments responses of two varieties of Catharanthus roseus to triadimefon treatment

Triadimefon, potential fungicide cum plant-growth retardant was used in this study to investigate its effect on the growth and the photosynthetic pigment contents of two varieties of Catharanthus roseus (L.) G. Don. The plants of both varieties were subjected to 15 mg l(-1) triadimefon treatment by soil drenching 30, 45, 60, and 75 days after planting (DAP). Plants were uprooted on 90 DAP, and morphological parameters, like plant height, number of leaves, leaf area, root length and fresh and dry weights were determined. The photosynthetic pigments, like chlorophylls a and b, total chlorophyll, carotenoids, floral pigment, anthocyanin, were extracted and estimated. It was observed that plant height, number of leaves and leaf area were decreased and that root length, fresh and dry weights were increased under triadimefon treatment. The photosynthetic and floral pigments were increased under triadimefon treatment in both varieties. The results suggest that the application of this plant-growth retardant (triadimefon) has favourable effects on the reduction of plant height; it can thus be used for replacing manual hand pruning and for improving floral and vegetation colour in bedding plants like C. roseus.     

Endogenous hormonal and enzymatic responses of Catharanthus roseus with triadimefon application under water deficits

The effect of triadimefon was investigated in a medicinal plant, Catharanthus roseus subjected to water deficit stress. The abscisic acid (ABA) level, DNA and RNA contents and activities of ATPase and protease were found varying in different parts of the plants under treatment. Drought treatment increased the ABA level more than twofold in all parts of the plants. TDM treatment to the drought stressed plants showed highest contents. In roots, stem and leaves, drought stress caused a decrease in the DNA and RNA contents when compared with control and other treatments. TDM treatment with drought increased the nucleic acid contents to the level of the control roots. The activity of ATPase and protease were increased under drought treatment and lowered due to TDM applications. This information could be useful in the field of soil water deficits reclamation efforts by using plant growth regulators.     

Differential responses in water use efficiency in two varieties of Catharanthus roseus under drought stress

Two varieties, rosea and alba, of Catharanthus roseus (L.) G. Don. were screened for their water use efficiency under two watering regimes, viz. 60 and 100% filed capacity in the present study. Drought stress was imposed at 60% filed capacity from 30 to 70 days after sowing, while the control pots were maintained at 100% filed capacity throughout the entire growth period. Leaf area duration, cumulative water transpired, water use efficiency, net assimilation rate, mean transpiration rate, harvest index, biomass and yield under the water deficit level were measured from both stressed and well-watered control plants. Water use efficiency significantly increased in both varieties under water stress. Drought stress decreased leaf area duration, cumulative water transpired, net assimilation rate, mean transpiration rate, harvest index, and biomass yield in both varieties studied. Among the varieties, rosea variety showed the best results.