New Metabolic/Physchem Data from Monash

[mattodd]

The latest data came back from CDCO a few days ago. Posted raw here. Summary image below. Previous consultation (#479) will be closed in a moment.

Observations on the data:

1) There is a range of human microsomal clearance rates. Good half lives seen for MMV897708, MMV688896, MMV670246, MMV670944. Uniformly high clearance in mouse microsomal assays, but perhaps this is not too important (as Paul mentioned)

2) LogD values generally slightly higher than cLogP. But not bad correlation.

3) Solubilities quite variable. Good levels seen for MMV688895.

4) Plasma protein binding: values range from 38 to 92%. Can someone with better knowledge of this than me please suggest an appropriate level for a lead antimalarial compound?

Best-performing compound is probably MMV688896. Modification of the alcohol functional group is a current target of Ed’s (#481).

To DO:

i) @edwintse @alintheopen please post the data to the Master List and reply below when done. Please also post the data to the daughter list for the Frontrunners, and post the link to that below when done.

ii) I will ensure the data are combined with what we already know of the properties of this series on the wiki.

iii) Which compounds to send for Aldehyde Oxidase assay: see #485

iv) Which compounds to evaluate further: (coming in a moment).

(Zip of CDCO Results Feb 2017.cdx.zip Chemdraw file of image if needed)

[edwintse]

All new Monash data has been added to the Master List.

[egonw]

What does the metabolic data look like? Is there overlap with what the XMetDb would record?

[alintheopen]

All data added to Master Chemical List and here is an updated 'daughter' Frontrunner list.

A few notes on the list above:

• MMV670652, MMV670437 and MMV669848 were inherited compounds and have not been resynthesised so were not assessed at Monash.

• EDIT The value for whole cell potency has been changed to the average value

• MMV670944 was resynthesised and retested. The data for this compound are highlighted in pale below because I've replaced the original values in the first 'daughter' frontrunner list. This can still be viewed in #400 Numbers file exported to Excel file attached below. Frontrunners Update Feb 2017.xlsx

[mattodd]

Useful additional comment by email from Scott Obach (Pfizer) 22/2/17: "There was a comment on protein binding 38-92% and what is a good value---this is a very difficult subject to address and describe but the real answer is that there is no “good” or “bad” value—it’s just important to know what fu value is so that in vivo efficacy and clearance differences among compounds can be explained and in vitro potency can be related to in vivo potency. Now that said, when things get bound up above 99%+, it gets a little harder to have confidence in the accuracy of measurement and in vitro-in vivo relationships can start getting clouded. But fu values ranging between 0.08 and 0.62 are all in the easy to interpret range and you wouldn’t want to select or prioritize compounds based on plasma fu. In fact, you may only want to collect that value when you intend to do some in vivo work and/or predict pharmacokinetics. In our department, we do not screen for fu. Despite being a straightforward measurement, there has always been a lot of confusion as to how it fits into drug research.”