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4th April 2014 @ 04:26

hERG data were obtained by MMV from Essen Bioscences. Report attached.

Summary:

MMV669844 and MMV670944 were both active in this assay with pIC50 values of 5.2 and 5.6.

And solubility issues were observed for compound MMV669844 at 33 uM in the final assay plate.

 

MMV669844 MMV670944 OSM-S-175

Preparation of OSM-S-175

Series 4 wiki

Data discussed briefly during OSM Online Project Meeting 7 (27th March 2014)

Linked Posts
Attached Files
17th February 2014 @ 05:20

Posted on behalf of Paul Willis

 

One member of the triazolopyrazines (Series 4) (MMV639565) had previously been evaluated in vivo and shown rapid parasite clearance. Data shown here.

Another member of the series (MMV669844) has now been tested in a snapshot (one dose level of 4 x 50 mg/Kg) efficacy SCID study at Swiss TPH. The compound had excellent efficacy as shown in the attached report (>99.9% inhibition of parasitimia) showing this appears a general property of the series.

MMV669844 and MMV639565

MMV669844_SCID.pdf

Attached Files
3rd February 2014 @ 10:59

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

MMV triazolopyrazine data

Linked Posts
16th January 2014 @ 05:57

Data derived from pre-OSM work on Series 4 amides. Was originally posted here, but posted here again as may be more suitable grouped with biological data.

Original spreadsheet:

Amides in TP series.xlsx

Wiki summary here.

Chemdraw file

Amide Library.cdx

Picture file

Amide Library.png

 

 

Strings:

MMV668958    N1=CC2=NN=C(N2C(=C1)C(=O)NCc1cc(ccc1)Cl)c1ccc(cc1)OC(F)F
MMV669000    N1=CC2=NN=C(N2C(=C1)C(=O)N1Cc2c(cccc2)C1)c1ccc(cc1)OC(F)F
MMV669001    N1=CC2=NN=C(N2C(=C1)C(=O)NCc1ccc(cc1)Cl)c1ccc(cc1)OC(F)F
MMV669002    N1=CC2=NN=C(N2C(=C1)C(=O)NCc1ccccc1Cl)c1ccc(cc1)OC(F)F
MMV669003    N1=CC2=NN=C(N2C(=C1)C(=O)NCC1CCOCC1)c1ccc(cc1)OC(F)F
MMV669010    N1=CC2=NN=C(N2C(=C1)C(=O)N1CCN(c2ncccc2)CC1)c1ccc(cc1)OC(F)F
MMV669011    N1=CC2=NN=C(N2C(=C1)C(=O)NCCN1CCOCC1)c1ccc(cc1)OC(F)F
MMV669022    N1=CC2=NN=C(N2C(=C1)C(=O)N1CCCC1)c1ccc(cc1)OC(F)F
MMV669104    N1(CCCC1c1ccccc1)C(=O)C1=CN=CC2=NN=C(N12)c1ccc(cc1)OC(F)F
MMV669023    N1(CCN(CC1)S(=O)(=O)C)C(=O)C1=CN=CC2=NN=C(N12)c1ccc(cc1)OC(F)F
MMV669020    N1(CCOCC1)C(=O)C1=CN=CC2=NN=C(N12)c1ccc(cc1)OC(F)F
MMV669024    N([C@H](c1ccccc1)C)C(=O)C1=CN=CC2=NN=C(N12)c1ccc(cc1)OC(F)F
MMV669021    N([C@@H](c1ccccc1)C)C(=O)C1=CN=CC2=NN=C(N12)c1ccc(cc1)OC(F)F
MMV669026    n1c(cccc1)NC(=O)C1=CN=CC2=NN=C(N12)c1ccc(cc1)OC(F)F
MMV669027    N(CCc1ccccc1)C(=O)C1=CN=CC2=NN=C(N12)c1ccc(cc1)OC(F)F
MMV669105    Clc1cc(ccc1)CN(C)C(=O)C1=CN=CC2=NN=C(N12)c1ccc(cc1)OC(F)F
MMV669543    n12c(cncc1nnc2c3ccc(cc3)OC(F)F)C(=O)NCc4ccc(c(c4)F)F
MMV669542    n12c(cncc1nnc2c3ccc(cc3)OC(F)F)C(=O)Nc4cccc(c4)Cl
MMV670246    c1ncc2nnc(n2c1C(Nc1ccc(cc1)Cl)=O)c1ccc(cc1)OC(F)F
MMV669849    c1ncc2nnc(n2c1C(Nc1ccc(cc1)F)=O)c1ccc(cc1)OC(F)F
MMV669850    c1ncc2nnc(n2c1C(Nc1ccc(c(c1)F)F)=O)c1ccc(cc1)OC(F)F
MMV670767    c1ncc2n(c1C(=O)Nc1ccc(c(c1)Cl)F)c(nn2)c1ccc(cc1)OC(F)F
MMV670944    c1ncc2n(c1C(=O)Nc1ccnc(c1)C(F)(F)F)c(nn2)c1ccc(cc1)OC(F)F
MMV670768    c1ncc2n(c1C(=O)N1CCc3c1ccc(c3)F)c(nn2)c1ccc(cc1)OC(F)F
MMV671654    c1ncc2n(c1C(=O)Nc1ccc(cc1Cl)F)c(nn2)c1ccc(cc1)OC(F)F
MMV671676    c1c(c(ccc1Cl)Cl)CNC(c1cncc2n1c(nn2)c1ccc(cc1)OC(F)F)=O
MMV671677    c1c(c(c(cc1)C(F)(F)F)Cl)CNC(c1cncc2n1c(nn2)c1ccc(cc1)OC(F)F)=O

Linked Posts
Attached Files
19th December 2013 @ 22:51

Three compounds sourced from MMV in the OSM Series 4 (the triazolopyrazines) were sent for metabolism ID testing at Monash University, to ID how these compounds were being metabolised as a guide for future analog design. Eight other compounds had displayed reasonably rapid clearance and low solubility.

 

Compounds sent for MetID

 

Data received Dec 19th 2013 and are attached to this post.

CDCO_MMV_OSDD_13_006_Hepatocyte stability and Met ID.pdf

Comments from Karen White: "The met ID study for 3 compounds in human and rat hepatocytes has now been completed and the results are summarised in the attached report. Regarding the aldehyde oxidase question, one of the compounds did form an oxygenated metabolite which may or may not be mediated by AO (can also be mediated by CYP enzymes) but we couldn’t definitively tell the site of oxygenation from the available data or the enzyme responsible."

Initial analysis from Paul Willis: "Metabolite ID has shown that the 3 compounds all appear to undergo oxidation on the triazolpyrazine ring.  This could be CYP or aldehyde oxidase mediated, further experiments are planned next year to determine which process is operating.  At this stage the project should evaluate the existing data to see if either changes to the bulk properties (Log P etc.) or remote changes can increase metabolic stability.  This may indicate a strategy for designing new more stable analogues.  Blocking groups could also be introduced into the labile positions of the triazolopyrazine ring to further improve metabolic strategy.  Given the likely synthetic challenges of such an approach, the project is recommended to wait until the full results of the metabolism experiments are available to guide such a strategy."

Results to be discussed in OSM project meeting on Dec 20th: OSM Online Project Meeting Six (20th December 2013)

 

 

Strings

MMV669844

[C@H](COc1cncc2n1c(nn2)c1ccc(cc1)C#N)(c1cc(c(cc1)F)F)OC

MMV669848

c1ncc2nnc(n2c1CN1Cc2c(C1)cccc2)c1ccc(cc1)OC(F)F

MMV670936

C(COc1cncc2n1c(nn2)c1cnc(cc1)C(F)(F)F)c1cc(c(cc1)F)F

Attached Files