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15th May 2012 @ 01:15
A p.o. P.Berghei mouse study at 50 mg/kg revealed no efficacy of OSM-S-35 (ZYH 3-1),OSM-S-5 (TCMDC-123812) or OSM-S-6 (TCMDC-123794) relative to control. Experiments carried out at Swiss TPH. Experiment start 23/04/12.

bioteststructures.png

Method Overview:
"This protocol is performed in the group of Dr Sergio Wittlin at Swiss TPH (Unit of Prof. Reto Brun), for assessing compound efficacy against the Plasmodium berghei GFP ANKA strain in-vivo. Mice are infected intravenously with parasitized red blood cells on day 0 (2 x 107 parasitized erythrocytes per ml). Experimental mice are generally treated at 4, 24, 48, and 72 hours post-infection with an oral dose of the compound (4-day test by Peters) and are compared to an infected control group for reduction in parasitaemia on day 4 (96 hours post-infection) in % and for mean survival (monitored up to 30 days post-infection). A compound is considered curative, if the animal survives to day 30 after infection with no detectable parasites. Other delivery route (intravenous, intraperitoneal, subcutaneous) and dosing regimen (e.g. single dose) are possible.

Percent activities below 40% are regarded as inactive.

To put the data into context, a new lead optimization project should typically show an oral ED50 <50mg/kg while a development candidate will typically have an oral ED90 <10mg/kg"

The raw data in excel format:
Raw Data
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14th May 2012 @ 23:53
Biological testing of the 2nd round of compounds reported on 05/05/12 by James S. Pham from the University of Melbourne.

Visual summary of results and compound structures:
Visual Summary


Methods Overview:
"Compounds were tested for inhibition of Plasmodium falciparum growth using a SYBR green I fluorescence based assay. Dose response curves were generated comprising of 8 points using a 2-fold serial dilution for the maximum final concentration of 1000 nM. The lowest concentration tested was 7.81 nM."

Raw Data originally posted on Google+ along with a detailed method description and report.

Raw data and graphs in excel format:
Raw Data and Graphs


Compounds tested:
PMY 12-5, PMY 27-2, PMY 31-5, PMY 34-1, ZYH 3-1, ZYH 5-1, ZYH 6-1/6-2, ZYH 7-2, ZYH 10-2 A, ZYH 10-2 B, ZYH 12-1/12-2, ZYH 15-1, ZYH 16-1, ZYH 17-1, ZYH 18-1, ZYH 19-1, ZYH 22-3, ZYH 23-1

Analysis of the same compounds:
Second Round of Evaluation by GSK Tres Cantos
Second Round of Evaluation by the Avery Lab

Results largely consistent with above analyses.
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7th May 2012 @ 12:35

Data acquired by Karen White External Projects Coordinator, Centre for Drug Candidate Optimisation, Monash Institute of Pharmaceutical Sciences, Monash University (Parkville Campus), 381 Royal Parade, Parkville, Victoria 3052, Australia

Compounds examined:

Compounds Examined in Metabolic Assays
Note scheme error: ZYH 6 compound is OSM-S-38, not 37.

Data (xls):

Metabolic Data

The 0-1.6 µg/mL window means that the solubility was less than the lowest concentration tested which in this assay is 1.6 µg/mL.

Conclusion: That some compounds displayed low degradation at the expense of low solubility.

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1st May 2012 @ 05:45

Data from Sandra Duffy, Griffith University Received April 25th 2012

Four compounds from the arylpyrrole series tested in a late stage anti-gametocyte imaging assay.

Relevant compounds:

Gametocyte Compounds
Note - mistake in picture ZHY 6 was sent, which is OSM-S-38, not OSM-S-37 as shown in the figure.


Method: The assay involves the use of a Pfs16-GFP transgenic NF54 Plasmodium falciparum strain kindly provided by Dr David Fidock (Columbia University). Compound is added to 384 well imaging plates containing 20,000 highly synchronous late stage IV gametocytes. The plates are incubated for 72 hours in standard incubation conditions (5%CO2, 5%O2, 37oC, 5% humidity). After incubation the viability marker MitoTracker Red CM-H 2 XRos is added to the wells. The plates are then imaged on the OPERA confocal high-throughput imaging system. The images obtained are then analysed using an algorithm for determining the number of viable gametocytes still remaining in the compound treated wells based on viability marker fluorescent intensity and the morphology of the GFP expressing parasite. The number of gametocytes per well in this assay is the same number of parasites used in the asexual imaging assay for 3D7 and K1. Results: PMY10-2 has no significant activity whilst PMY14-1 has activity comparable to that in the asexual assay. (MHT: Others?)

Raw data:

Gametocyte Assay
Caveat: It has to be noted that the compounds have been in storage for a while and the plates defrosted several times for screening. The inactive compound could have lost asexual activity at the same time due to some instability. This was not tested.
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