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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

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11th December 2013 @ 07:31

Professor Sue Charman's team (Monash University) have conducted physiochemical evaluation and metabolism studies for the following eight compounds:

Physiochemical Evaluation

Study Objective: To evaluate the physicochemical properties of the selected compounds.

CDCO_MMV_OSDD_13_004_Chem.pdf

Metabolism in Human and Mouse Liver Microsomes

Study Objective: To determine the in vitro metabolic stability of the selected compounds using human and mouse liver microsomes as a preliminary indication of the likely in vivo metabolic clearance.

CDCO_MMV_OSDD_13_005_Met.pdf

Analysis:

Paul Willis made the following conclusions from the studies:

'Solubility is low and improvement should be one of the goals for LO. The metabolic stability is not a mouse specific event and needs to be improved to deliver a candidate – the met ID data will follow and may help in the design of new, analogues with improved stability (but we could also look at correlations with Log D etc. to drive new target design)'

Data:

Strings:

MMV668957

InChI=1S/C22H19F2N5O/c23-22(24)30-18-8-6-16(7-9-18)21-27-26-19-12-25-13-20(29(19)21)28-11-10-17(14-28)15-4-2-1-3-5-15/h1-9,12-13,17,22H,10-11,14H2

MMV668958

InChI=1S/C20H14ClF2N5O2/c21-14-3-1-2-12(8-14)9-25-19(29)16-10-24-11-17-26-27-18(28(16)17)13-4-6-15(7-5-13)30-20(22)23/h1-8,10-11,20H,9H2,(H,25,29)

MMV669304

InChI=1S/C21H18F2N4O/c22-21(23)28-18-11-9-16(10-12-18)20-26-25-19-14-24-13-17(27(19)20)8-4-7-15-5-2-1-3-6-15/h1-3,5-6,9-14,21H,4,7-8H2

MMV670438

InChI=1S/C22H16F4N4O3/c23-16-6-3-14(7-17(16)24)22(10-31-11-22)12-32-19-9-27-8-18-28-29-20(30(18)19)13-1-4-15(5-2-13)33-21(25)26/h1-9,21H,10-12H2

MMV670944

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)

MMV671651

InChI=1S/C20H15F4N5O2/c21-14-6-3-12(7-15(14)22)16(25)10-30-18-9-26-8-17-27-28-19(29(17)18)11-1-4-13(5-2-11)31-20(23)24/h1-9,16,20H,10,25H2/t16-/m0/s1

MMV672723

InChI=1S/C21H16F4N4O3/c1-21(30,13-4-7-15(22)16(23)8-13)11-31-18-10-26-9-17-27-28-19(29(17)18)12-2-5-14(6-3-12)32-20(24)25/h2-10,20,30H,11H2,1H3

MMV672727

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






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