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Data obtained at the outset of Series 4 included potency and PK data, but no formal record of how the data were obtained - i.e. details of assays. Paul Willis wrote on 3rd Feb 2014 by email to provide the following methods:
1. Parasite assay - In Vitro EC50 (uM) (Erythrocyte assay - NF54 with 3H-Hypoxanthine at 72hr time point)
2. Rat and human liver microsomes - Test compound is incubated with pooled human (or rat) liver microsomes in 100 mM phosphate buffer (pH 7.4) at 37°C in the presence of NADP cofactor. The incubation volume is 0.1 mL. Test compounds are tested at 1 mM.
These assays will need to be linked with the data upon upload to ChEMBL following assignment of OSM numbers.
Inherited Data on Series 4 Amides
Collected Amides in the TP Series (Triazolopyrazines, Series 4)
A New Triazolopyrazine Series for OSM - Series 4
Biological evaluation of OSM-S-117 through 138 (also OSM-S-107) performed in Vicky Avery's lab by Sabine Fletcher.
Data for previous OSM-S compounds can be found here - OSM Compound List
Unfortunately only two (OSM-S- 137 and 138) were active on 3D7.
The summary also contains information about the solubility: several of the compounds turned opaque when diluted down to 4% DMSO, which suggests poor solubility in this condition. I made sure to mix the compounds very well before the final 1:10 dilution step in the assay plate.
One compound (OSM-S-134) did not dissolve well in 100% DMSO. It still contained many needle-like crystals after shaking over night, which means that we do not know the actual concentration of the dissolved compound in the assay. As tested here, it was completely inactive.
Click for larger image
Click for larger image
Depictions of Data including cLogP values and comments on solubility:
Activities of hit vs simple analogs
Variation of amine to morpholine
Variation in amine component
Comparison with known other TCMDC hits
Biological evaluation of OSM-S-106 through 116 (excluding OSM-S-107) performed in Vicky Avery's lab by Sabine Fletcher.
The compounds look good in this round - all but cpd OSM-S-113 show activity.
I already ran the cytotoxicity as well, and none of the compounds was particularly cytotoxic (see 'summary report' file and curves in PDF).
Solubility: minor floating specks after dissolving in OSM-S-106; all others fine
Unfortunately I made a minor mistake: I started the Artemisinin CRC curve at the wrong concentration, 40 uM (same concentration as the compounds) as opposed to the usual 2 uM. The IC50 value obtained for the control is correct (4 nM), just the x-axis range of the curve is different compared to the previous runs. Sorry for that!
Displacement Curves
Strings
| ID | InChI | 3D7 IC50 (nM) |
| OSM-S-106 | InChI=1S/C12H10N4O2S2/c13-12-11-9(15-6-16-12)5-10(19-11)7-2-1-3-8(4-7)20(14,17)18/h1-6H,(H2,13,15,16)(H2,14,17,18) | 36 |
| OSM-S-108 | InChI=1S/C16H15N3OS/c1-10-8-12(11(2)17-10)9-14-15(20)19-16(21-14)18-13-6-4-3-5-7-13/h3-9,17H,1-2H3,(H,18,19,20)/b14-9- | 1200 |
| OSM-S-109 | InChI=1S/C22H18N4O3S/c1-14-12-16(15(2)25(14)18-8-10-19(11-9-18)26(28)29)13-20-21(27)24-22(30-20)23-17-6-4-3-5-7-17/h3-13H,1-2H3,(H,23,24,27)/b20-13- | 262 |
| OSM-S-110 | InChI=1S/C22H18N4O4S/c1-13-10-15(14(2)25(13)17-6-8-18(9-7-17)26(29)30)11-20-21(28)24-22(31-20)23-16-4-3-5-19(27)12-16/h3-12,27H,1-2H3,(H,23,24,28)/b20-11- | 2300 |
| OSM-S-111 | InChI=1S/C23H21N3O2S/c1-15-13-17(16(2)26(15)19-9-11-20(28-3)12-10-19)14-21-22(27)25-23(29-21)24-18-7-5-4-6-8-18/h4-14H,1-3H3,(H,24,25,27)/b21-14- | 146 |
| OSM-S-112 |
InChI=1S/C23H21N3O3S/c1-14-11-16(15(2)26(14)18-7-9-20(29-3)10-8-18)12-21-22(28)25-23(30-21)24-17-5-4-6-19(27)13-17/h4-13,27H,1-3H3,(H,24,25,28)/b21-12- |
1600 |
| OSM-S-113 | InChI=1S/C21H18N4O2S/c1-13-11-15(14(2)25(13)19-5-3-4-10-22-19)12-18-20(27)24-21(28-18)23-16-6-8-17(26)9-7-16/h3-12,26H,1-2H3,(H,23,24,27)/b18-12- | >40,000 |
| OSM-S-114 |
InChI=1S/C22H19N3O2S/c1-14-11-16(15(2)25(14)18-8-4-3-5-9-18)12-20-21(27)24-22(28-20)23-17-7-6-10-19(26)13-17/h3-13,26H,1-2H3,(H,23,24,27)/b20-12- |
1200 |
| OSM-S-115 |
InChI=1S/C22H19N3O2S/c1-14-12-16(15(2)25(14)18-6-4-3-5-7-18)13-20-21(27)24-22(28-20)23-17-8-10-19(26)11-9-17/h3-13,26H,1-2H3,(H,23,24,27)/b20-13- |
1800 |
| OSM-S-35 | InChI=1S/C22H19N3OS/c1-15-13-17(16(2)25(15)19-11-7-4-8-12-19)14-20-21(26)24-22(27-20)23-18-9-5-3-6-10-18/h3-14H,1-2H3,(H,23,24,26)/b20-14- | 38 |
| OSM-S-116 | InChI=1S/C16H17FN2O3/c1-9-8-14(16(21)22-11(3)15(18)20)10(2)19(9)13-6-4-12(17)5-7-13/h4-8,11H,1-3H3,(H2,18,20) | 11000 |
Glutathione Trapping Study for OSM-S-35
Results
Conclusion
We’ve run the glutathione trapping study for OSM-S-35 in the presence of metabolic activation (i.e. human microsomes). We also included a search for other potential metabolites formed. A number of metabolites were detected, mainly oxygenated species (mono, bis and tri-oxygenated metabolites) with the predominant metabolite (based on peak area and assuming similar response factors for each metabolite) arising from likely hydroxylation of the pyrrole substituted benzene. In the presence of GSH-EE, adducts were observed both in the presence and absence of metabolic activation. The results are summarised in the attached file. Please let me or Sue know if you have any questions or comments
