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17th November 2014 @ 17:48

A set of 12 compounds were sent to Syngene for evaluation against blood stage asexual NF54 strain of Plasmodium falciparum.

Samples sent for in vitro efficacy evaluation against Plasmodium falciparum asexual blood stage

Data were received (via the ScienceCloud portal at MMV) on October 10th. Data for one compound was missing, and subsequently received on Oct 23rd. Data:

Syngene Data Oct 2014

Observations:

1. CF3 tolerated as a replacement for CHF2 in northeast, which may make synthesis simpler. Impact of using Me looks to be to reduce potency.

Impact of CH3 vs CF3 vs CHF2

(Note - need analysis along similar lines for impact of Cl and CN)


2. High sensitivity to changes in northwest ring. Compare MMV675951 and MMV675950

 

3. Pyridyl is a bad substitution. Compare MMV675963 with MMV675961, MMV675962. Also compare MMV675949 with OSM-S-189.


4. Benzylic in northwest not bad, but deleterious compared to phenethyl (MMV639565, 38 nM).

 

This post originally authored by Mat Todd

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16th November 2014 @ 22:57

Context: 12 compounds were sent for evaluation for metabolic clearance by aldehyde oxidase (Discussion, Compounds sent:

Which Compounds to Send for Aldehyde Oxidase Assay?

Assay performed by: Christine Orozco, Scott Obach, Pfizer, Groton CT.

Results:

Aldehyde Oxidase Results OSM Series 4


Notes:


The compounds were incubated in 1 mg/mL cytosol out to 3 hours. Controls: carbazeran, zoniporide and zaleplon were assayed in each incubation plate to represent high, moderate and low AO clearance respectively. The Open Source Malaria compounds were assayed along with the controls and compared using a relative yardstick approach.

The test compounds had a range of clearances. There was one high clearance compound similar to carbazeran, three moderate clearance compounds similar to zoniporide, two compounds with moderate to low clearance, and the remaining four compounds were stable/low clearance with no turnover within 3 hours.

Two compounds were not included for technical reasons. Compound MMV670250 was not detected under the analytical methods used so new LC/MS methods are being developed for this compound. For MMV672939, there was variability in the later time points of both replicates. These two compounds can be repeated in the future.


More detail on the data, protocol, assay notes and conditions is in the attached spreadsheet.

OpenSource Malaria_Cytosol_Results_Protocol_CCO.xlsx

This post originally authored by Mat Todd


Strings:
MMV668956 FC(F)OC(C=C1)=CC=C1C2=NN=C(N32)C=NC=C3OC4CN(C5=CC(F)=C(F)C=C5)C4 InChI=1S/C21H15F4N5O2/c22-16-6-3-13(7-17(16)23)29-10-15(11-29)31-19-9-26-8-18-27-28-20(30(18)19)12-1-4-14(5-2-12)32-21(24)25/h1-9,15,21H,10-11H2 FFDOLPKXJUAFAH-UHFFFAOYSA-N
MMV669784 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=NC=C(OC4=CC=C(Cl)C=C4)N32 InChI=1S/C18H11ClF2N4O2/c19-12-3-7-13(8-4-12)26-16-10-22-9-15-23-24-17(25(15)16)11-1-5-14(6-2-11)27-18(20)21/h1-10,18H WXNPYOXFQUYIOI-UHFFFAOYSA-N
MMV669844 FC(C=C1)=C(F)C=C1[C@@H](OC)COC2=CN=CC3=NN=C(C4=CC=C(C#N)C=C4)N32 InChI=1S/C21H15F2N5O2/c1-29-18(15-6-7-16(22)17(23)8-15)12-30-20-11-25-10-19-26-27-21(28(19)20)14-4-2-13(9-24)3-5-14/h2-8,10-11,18H,12H2,1H3/t18-/m0/s1 PERKBMZWWUEZNJ-SFHVURJKSA-N
MMV669846 FC1=C(F)C=CC(CCOC2=CN=CC3=NC=C(C4=CC=C(Cl)C=C4)N32)=C1 InChI=1S/C20H14ClF2N3O/c21-15-4-2-14(3-5-15)18-10-25-19-11-24-12-20(26(18)19)27-8-7-13-1-6-16(22)17(23)9-13/h1-6,9-12H,7-8H2 MQHQNFQVEXYAMO-UHFFFAOYSA-N
MMV670947 FC(F)OC(C=C1)=CC=C1C2=NN=C(N32)C=NC=C3OCC(CO)C4=CC=C(F)C(F)=C4 InChI=1S/C21H16F4N4O3/c22-16-6-3-13(7-17(16)23)14(10-30)11-31-19-9-26-8-18-27-28-20(29(18)19)12-1-4-15(5-2-12)32-21(24)25/h1-9,14,21,30H,10-11H2 MKSKANAVVSFYNL-UHFFFAOYSA-N
MMV670246 FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C(C(NC4=CC=C(Cl)C=C4)=O)=CN=C3 InChI=1S/C19H12ClF2N5O2/c20-12-3-5-13(6-4-12)24-18(28)15-9-23-10-16-25-26-17(27(15)16)11-1-7-14(8-2-11)29-19(21)22/h1-10,19H,(H,24,28) CAFUHAVOTBMKAN-UHFFFAOYSA-N
MMV670250 FC1=C(F)C=CC(CCOC2=CN=CC3=CN=C(C4=CC=C(Cl)C=C4)N32)=C1 InChI=1S/C20H14ClF2N3O/c21-15-4-2-14(3-5-15)20-25-11-16-10-24-12-19(26(16)20)27-8-7-13-1-6-17(22)18(23)9-13/h1-6,9-12H,7-8H2 JHORUMGXLQTHAD-UHFFFAOYSA-N
MMV670944 FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C(C(NC4=CC=NC(F)=C4)=O)=CN=C3 InChI=1S/C18H11F3N6O2/c19-14-7-11(5-6-23-14)24-17(28)13-8-22-9-15-25-26-16(27(13)15)10-1-3-12(4-2-10)29-18(20)21/h1-9,18H,(H,23,24,28) UEOZBGRWGZEYED-UHFFFAOYSA-N
MMV670946 FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C=C(OCC4=CC=C(F)C(F)=C4)N=C3 InChI=1S/C19H12F4N4O2/c20-14-6-1-11(7-15(14)21)10-28-17-9-27-16(8-24-17)25-26-18(27)12-2-4-13(5-3-12)29-19(22)23/h1-9,19H,10H2 PPYIQNQWTQZDBZ-UHFFFAOYSA-N
MMV671927 FC(F)OC(C=C1)=CC=C1C2=NN=C3N2C=C(NCCC4=CC=C(F)C(F)=C4)N=C3 InChI=1S/C20H15F4N5O/c21-15-6-1-12(9-16(15)22)7-8-25-17-11-29-18(10-26-17)27-28-19(29)13-2-4-14(5-3-13)30-20(23)24/h1-6,9-11,20,25H,7-8H2 GVXYAEXVJYZTBB-UHFFFAOYSA-N
MMV672727 FC(F)OC(C=C1)=CC=C1C2=NN=C(N32)C=NC=C3OCC(F)(C)C4=CC=C(F)C(F)=C4 InChI=1S/C21H15F5N4O2/c1-21(26,13-4-7-15(22)16(23)8-13)11-31-18-10-27-9-17-28-29-19(30(17)18)12-2-5-14(6-3-12)32-20(24)25/h2-10,20H,11H2,1H3 MHMDPQOWBHVFHN-UHFFFAOYSA-N
MMV672939 FC(F)OC(C=C1)=CC=C1C2=NN=C3C=CC(OCCC4=CC(F)=C(F)C=C4)=NN32 InChI=1S/C20H14F4N4O2/c21-15-6-1-12(11-16(15)22)9-10-29-18-8-7-17-25-26-19(28(17)27-18)13-2-4-14(5-3-13)30-20(23)24/h1-8,11,20H,9-10H2 POGWIRSWBGSGTG-UHFFFAOYSA-N

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