S4 data Indirectly from MCPHS.

[cdsouthan]

Due to personal exigencies @MedChemProf cannot upload directly and has therefore passed along a data sheet from some months back. It contains a few matched pairs in a metabolic study by Forma Therapeutics (MA). Take home is the di-fluoro offers very little to no added metabolic stability. The extra fluoro is just negatively contributing to the LogP. Chase hopes to return to previous participation levels in 2Q 2018. Please don't bother with questions to me as I cannot answer them.

OSM_HLM_MLM.xlsx

[MFernflower]

Data in image format for easy viewing:

A few other things can be gleaned from the test results: 1: Ethers are better than amides in terms of resistance to human first-pass (seems obvious but good to have concrete data!) 2: 4-cyano seems to have advantages over 4-methylsulfone and 4-chloro - Does potency take a hit from OCHF2 --> CN swap?

From the data presented here I hereby propose a few new compounds: - Any takers?

https://www.enaminestore.com/catalog/EN300-61341 ---> Link for cyanophenethanol fragment (A bit pricey from enamine at 131 usd a gram) ---> Does uSyd have any in stock or does it need to be ordered? @mattodd

Update 12/7/17: Please disregard the two sulfur containing molecules as I cannot find the alcohol fragment anywhere and they would need to be made from scratch probably using very foul smelling chemicals

This could be an artifact from SwissADME but the difference in greasiness is impressive:

[mattodd]

Thanks for posting @cdsouthan and analysing @MFernflower . To my mind we're still in the "these molecules are quite greasy and suffer from fairly rapid clearance" zone. What are the predicted logPs for your suggested compounds @MFernflower ?

It still seems to me that we need to be getting the aqueous solubility up as a generic strategy towards lowering clearance rates - hence the interest in the compounds over at #555 . We're waiting on data from Dundee on potency of the latest compounds but if more water soluble compounds are potent we will need to secure data on clearance rates (and measured logD values) for those. We've a slot booked in Sue Charman's lab in Feb for a set of about 8 compounds - we'll consult on this when we have the Dundee data.

[MFernflower]

Attached is a csv file contaning predictions made by swissadme for the two compounds I wish to propose: @mattodd / @david1597 swissadme.csv.txt

[mattodd]

Ok @MFernflower but if we're up at around 4 on logP and we're doing slight alterations to the periphery I'm pessimistic we'll solve these clearance issues (particularly when judged by the resources needed to make another molecule). We need to get the logP significantly down if we're going to explore this hypothesis (that better solubility will also deal with clearance) adequately. The biggest remaining liability of the series is not potency. Chase's data for me complement what we already have, and strengthen the desirability of slightly more radical alterations. Installing an alcohol in the benzylic position as per targets in #555 would help, and the cyano could be a fragment we look at in that context, obviously.

[mattodd]

FYI file backed up here.