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11th July 2013 @ 10:13

Biological evaluation of OSM-E-4 through 8 performed at the Dundee Drug Discovery Unit by Irene Hallyburton.

Unfortunately all five compounds tested were inactive, possibly with some low activity at maximum doses (0.05 mM) although this may be an artifact of the fitting.

OSM-E-4 was dosed according to concentrations calculated with a molecular weight of 240 rather than 314 due to inconsistent mass specta available when samples were sent to Dundee.

Given that OSM-E-4 is inactive, I do not recommend that this sample is rerun: Tthe consequence of this miscalculation is that the lower limit of activity is even higher than normal and this compound is extra-specially inactive.

 

 

OSM-E-4 through OSM-E-8.pdf

 

Synthetic procedures: OSM-E-4 through 7 were synthesised in one experiment: Synthesis of PT-1-14 and OSM-E-8 was synthesised here: Amidation of PT-1-14C3 (PT-1-15)

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3rd July 2013 @ 02:03

Performed by Sue Charman's laboratory at the CDCO at Monash University.

Two compounds, OSM-S-106 and OSM-S-111, which possessed favourable activity have been assessed in assays designed to probe metabolic stability and measure kinetic stability.

Assay Details (provided by Karen White at Centre for Drug Candidate Optimisation, Monash University, 17th July 2013)

General method for assessing kinetic solubility

DMSO solutions of each test compound are spiked (at a 1:100 dilution) into aqueous test media (pH 2 and 6.5) in a 96-well plate. The final concentrations of compound in the test media typically span the range of 1.6 – 100 µg/mL. Plates are allowed to stand for
30 minutes at room temperature, after which the extent of compound precipitation is measured by nephelometry. The kinetic solubility limit is determined by the compound concentration at which precipitation becomes evident.

 General method for metabolism studies conducted in hepatic microsomes

A solution of each test compound (and quality control compounds) prepared in 50% acetonitrile/water is spiked into microsomal matrix (microsomes suspended in phosphate buffer) and incubated at 37°C. The reaction is initiated by the addition of NADPH (the cofactor for CYP450-mediated metabolism) and then the reaction is quenched at various time points over a 60 minute incubation period by the addition of ice-cold acetonitrile. Additional control samples are also included to monitor for potential compound degradation in the absence of cofactor. Quenched samples are analysed by UPLC-MS to determine the extent and rate of loss of parent compound. The depletion rate constant for each compound is then used to calculate a degradation half-life and in vitro intrinsic clearance.

Metabolic Data:

received 21st June 2013

CDCO_MMV_OSDD_13_002_Met.xlsx

 

Kinetic Solubility Data:

received 1st July 2013

CDCO_MMV_OSDD_13_003_Chem.xlsx

 

 

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