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12th September 2016 @ 12:55

Haochuan's attempts at forming crystals of HM 3-2 were successful. The structure was detemined by Peter Turner of the X-ray Crystal Structure Facility in the School of Chemistry, University of Sydney, and forwarded to the group by email on Sept 1st 2016. Files appended.

HM 3-2

 

3-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyrazine

BrC1=NN=C2C=NC=C(Cl)N21

InChI=1S/C5H2BrClN4/c6-5-10-9-4-2-8-1-3(7)11(4)5/h1-2H

UGKMQVWBWSZEBB-UHFFFAOYSA-N

Synthesis of 3-bromo-5-chloro-[1,2,4]triazolo[4,3-a]pyrazine (HM 3-2)

Crystallizing HM 3-2

Attached Files
1st February 2014 @ 00:41

This paper from Novartis/Scripps/MMV describes a compound (KAI407) effective against a model of P. vivax. There are obvious similarities (gut-feeling, not quantified or substantiated) between this compound and OSM's Series 4:

OSM Series 4 vs KAI407

The known SAR is shown in more detail on the Series 4 wiki, in particular what is known of transposing ring nitrogens and the pendant chain on the pyrazine ring.

Action item was raised on Github here to evaluate whether to run some Series 4 compounds in the same assay.

 

(Note the Novartis compound is KAI (the letter i) not KA1 (the number 1) - important for search purposes)

Update/Answer - From Paul Willis by email March 5th:

These Novartis compounds that bear some similarity to OSM's Series 4 do not appear to hit PfATP4 (the suspected target of Series 4) – i.e. it has been evaluated for this. Data in the Novartis Nature paper [10.1038/nature12782] shows the MOA of the compounds is PI4K. There is also data in the paper (Extended Data Figure 5A) which tests a PfATP4 inhibitor against PI4K mutants, showing no cross resistance, suggesting a different MOA. From the paper, imidazopyrazines KDU691 and KDU751 are active against Py liver schizonts.  We now have data [spreadsheet attached to this post:

U Sydney liver data.xlsx
] showing the OSM compounds MMV669844 and MMV670944 are v weakly active against Pb liver schizonts (and a big difference from blood potency). Novartis will be unaware which OSM Series 4 compounds have been tested as MMV coordinates the screening of non-Novartis compounds in these screens.

To date, there appears good evidence that the OSM series does not share the same mechanism as the Novartis compounds highlighted: The Novartis imidazopyrazines are reported active against all liver stages in several Plasmodium species, including hypnozoites. For completeness this month, the two OSM compounds will be progressed into the Pc hypnozoite assay mentioned in the Novartis paper.

 

 

Strings:

KAI407

O=C(N(C1=CC=C(C#N)C=C1)C)C(N=C2)=CN3C2=NC=C3C4=CC=C(C(F)(F)F)C=C4

InChI=1S/C22H14F3N5O/c1-29(17-8-2-14(10-26)3-9-17)21(31)18-13-30-19(11-28-20(30)12-27-18)15-4-6-16(7-5-15)22(23,24)25/h2-9,11-13H,1H3

XAZOWMVYGFASLH-UHFFFAOYSA-N

MMV669542

O=C(NC1=CC=CC(Cl)=C1)C2=CN=CC3=NN=C(C4=CC=C(OC(F)F)C=C4)N32

InChI=1S/C19H12ClF2N5O2/c20-12-2-1-3-13(8-12)24-18(28)15-9-23-10-16-25-26-17(27(15)16)11-4-6-14(7-5-11)29-19(21)22/h1-10,19H,(H,24,28)

AJGOFYWOTIIYLR-UHFFFAOYSA-N

MMV669846

ClC(C=C1)=CC=C1C2=CN=C3C=NC=C(OCCC4=CC=C(F)C(F)=C4)N32

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

Linked Posts
Attached Files
21st October 2013 @ 04:33

Clarification of structures referred to as "amides" in briefing document at A New Triazolopyrazine Series for OSM - Series 4.

Structures:

 

Amide Clarification.png

Relevant data are in the appended spreadsheets. The data need to be incorporated into the larger spreadsheet for this series.

Data received via email from Paul Willis at MMV on Oct 10th 2013.

InChIs:

InChI=1S/C19H11F5N6O2/c20-18(21)32-12-3-1-10(2-4-12)16-29-28-15-9-25-8-13(30(15)16)17(31)27-11-5-6-26-14(7-11)19(22,23)24/h1-9,18H,(H,26,27,31)

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)

Attached Files