{"action":"created","issue":{"url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/388","repository_url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List","labels_url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/388/labels{/name}","comments_url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/388/comments","events_url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/388/events","html_url":"https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/388","id":154949545,"number":388,"title":"Meeting Discussion Point 1: Solubility","user":{"login":"mattodd","id":4386101,"avatar_url":"https://avatars.githubusercontent.com/u/4386101?v=3","gravatar_id":"","url":"https://api.github.com/users/mattodd","html_url":"https://github.com/mattodd","followers_url":"https://api.github.com/users/mattodd/followers","following_url":"https://api.github.com/users/mattodd/following{/other_user}","gists_url":"https://api.github.com/users/mattodd/gists{/gist_id}","starred_url":"https://api.github.com/users/mattodd/starred{/owner}{/repo}","subscriptions_url":"https://api.github.com/users/mattodd/subscriptions","organizations_url":"https://api.github.com/users/mattodd/orgs","repos_url":"https://api.github.com/users/mattodd/repos","events_url":"https://api.github.com/users/mattodd/events{/privacy}","received_events_url":"https://api.github.com/users/mattodd/received_events","type":"User","site_admin":false},"labels":[{"id":39019570,"url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/labels/question","name":"question","color":"cc317c","default":true},{"id":75244545,"url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/labels/Series%204","name":"Series 4","color":"8A0829","default":false}],"state":"open","locked":false,"assignee":{"login":"mattodd","id":4386101,"avatar_url":"https://avatars.githubusercontent.com/u/4386101?v=3","gravatar_id":"","url":"https://api.github.com/users/mattodd","html_url":"https://github.com/mattodd","followers_url":"https://api.github.com/users/mattodd/followers","following_url":"https://api.github.com/users/mattodd/following{/other_user}","gists_url":"https://api.github.com/users/mattodd/gists{/gist_id}","starred_url":"https://api.github.com/users/mattodd/starred{/owner}{/repo}","subscriptions_url":"https://api.github.com/users/mattodd/subscriptions","organizations_url":"https://api.github.com/users/mattodd/orgs","repos_url":"https://api.github.com/users/mattodd/repos","events_url":"https://api.github.com/users/mattodd/events{/privacy}","received_events_url":"https://api.github.com/users/mattodd/received_events","type":"User","site_admin":false},"assignees":[{"login":"mattodd","id":4386101,"avatar_url":"https://avatars.githubusercontent.com/u/4386101?v=3","gravatar_id":"","url":"https://api.github.com/users/mattodd","html_url":"https://github.com/mattodd","followers_url":"https://api.github.com/users/mattodd/followers","following_url":"https://api.github.com/users/mattodd/following{/other_user}","gists_url":"https://api.github.com/users/mattodd/gists{/gist_id}","starred_url":"https://api.github.com/users/mattodd/starred{/owner}{/repo}","subscriptions_url":"https://api.github.com/users/mattodd/subscriptions","organizations_url":"https://api.github.com/users/mattodd/orgs","repos_url":"https://api.github.com/users/mattodd/repos","events_url":"https://api.github.com/users/mattodd/events{/privacy}","received_events_url":"https://api.github.com/users/mattodd/received_events","type":"User","site_admin":false}],"milestone":null,"comments":21,"created_at":"2016-05-16T02:27:27Z","updated_at":"2016-11-11T09:07:21Z","closed_at":null,"body":"Background to Meeting on May 24th 2016  (#386).\n\n**Question**: Are we right to target improved aqueous solubility as our key strategy?\n**Question**: Might improvements in aqueous solubility also improve (slow down) metabolic clearance?\n**Question**: What are the best strategies for improving the solubility of new Series 4 analogs?\n**Question**: Is the informal cLogP cutoff value of 3.5 for new analogs in this series wise?\n### Resources:\n\nOSM [Series 4 summary wiki](http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series)\nLab books: [Labtrove](http://malaria.ourexperiment.org/?allblogs), Labarchives ([Ed Tse](https://au-mynotebook.labarchives.com/share/Edwin%2520Tse/MTYzLjh8MTUwOS8xMjYvVHJlZU5vZGUvMjUxNDEwNDEwOHw0MTUuOA==), [Chase Smith](https://mynotebook.labarchives.com/share/MCPHS%2520MedChem/MzUxLjB8MzY3Ny8yNzAvVHJlZU5vZGUvNDA0ODg3Njc4OHw4OTEuMA==)).\nCompound Database: [All OSM Compounds in Google Sheet](http://tinyurl.com/OSM-Compounds), [interactive view on Cheminfo](http://www.cheminfo.org/flavor/malaria/Display_data.html), [direct download of Series 4 SDF](http://malaria.ourexperiment.org/data/files/17162/malaria-2016-05-18.sdf).\n\nAs discussed at #333, we have measured logD data and metabolic clearance data for [8 compounds in Series 4](http://malaria.ourexperiment.org/biological_data/8408/post.html), from Monash. The data are all contained in the [main sheet](http://tinyurl.com/OSM-Compounds), but the relevant data are also in [this daughter sheet](https://docs.google.com/spreadsheets/d/150fcu87mV51yIECpeDGpGitwcb_CGLyfVmB4x37aYqE/edit?usp=sharing) for convenience. @MJTarnowski 's analysis suggested a logD - clearance correlation. @drc007 showed that Chemaxon gave good predicted logD values.\n\n_Comments/suggestions below are welcome, as well as (briefly please) during the webinar meeting and its follow-up (#394)._\n## Relevant background:\n\n1) Many of the most potent Series 4 compounds have cLogP values of > 4, e.g. MMV639565, below.\n2) What is known of metabolic clearance is on the [wiki](http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Physicochem.2Fmetabolism.2FPK), summarised in [this post](http://malaria.ourexperiment.org/biological_data/8225/Summary_of_Series_4_Metabolic_Data__July_2015.html), and was discussed at the [last online meeting](http://malaria.ourexperiment.org/osddmalaria_meeting_/8194/OSM_Online_Meeting_10_July_27th_2015.html). It seems as though traditional blocking strategies do not lead to significant improvements in metabolic parameters. \n3) A solution might be to increase aqueous solubility, invoking the assumption that this will lead to reduced clearance by CYP-related processes.\n4) We have informally adopted a maximum cLogP of 3.5 for new analogs in this Series, unless the compound is needed to answer some other question.\n5) Addition of polar groups to the northwest and northeast have resulted in potent compounds with better predicted solubility (e.g. alcohols in northwest sidechains in compounds MMV672687, MMV672723, MMV670947 (below)), but other strategies along these lines have obliterated potency (e.g. MMV670936, though [unsubstituted pyridine in northeast is bad](http://openwetware.org/wiki/Image:Aromatic_Variants_in_Northeast.png)).\n6) The amide sub-series of Series 4 was de-prioritised when these compounds appeared to show increased susceptibility to [aldehyde oxidase](http://openwetware.org/wiki/OpenSourceMalaria:Triazolopyrazine_%28TP%29_Series#Aldehyde_Oxidase_Assay) activity, probably arising from the electron-deficient triazolopyrazine ring. The reversed amide or Burns analogs (#390) might be appropriate isosteres should we decide to return to such compounds.\n7) Current compounds being made in this space include cubane analogs and oxidised sulfur side chains (#390) to attempt to deplanarise and/or increase solubility.\n\n**Question remains**: do people have suggestions for more polar groups that could be included (with literature justification for such targets being sound suggestions). \n![solubility examples](https://cloud.githubusercontent.com/assets/4386101/15380718/25dc5ef6-1dbc-11e6-9372-e39b14685fdd.jpg)\n"},"comment":{"url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/comments/259913277","html_url":"https://github.com/OpenSourceMalaria/OSM_To_Do_List/issues/388#issuecomment-259913277","issue_url":"https://api.github.com/repos/OpenSourceMalaria/OSM_To_Do_List/issues/388","id":259913277,"user":{"login":"drc007","id":7080516,"avatar_url":"https://avatars.githubusercontent.com/u/7080516?v=3","gravatar_id":"","url":"https://api.github.com/users/drc007","html_url":"https://github.com/drc007","followers_url":"https://api.github.com/users/drc007/followers","following_url":"https://api.github.com/users/drc007/following{/other_user}","gists_url":"https://api.github.com/users/drc007/gists{/gist_id}","starred_url":"https://api.github.com/users/drc007/starred{/owner}{/repo}","subscriptions_url":"https://api.github.com/users/drc007/subscriptions","organizations_url":"https://api.github.com/users/drc007/orgs","repos_url":"https://api.github.com/users/drc007/repos","events_url":"https://api.github.com/users/drc007/events{/privacy}","received_events_url":"https://api.github.com/users/drc007/received_events","type":"User","site_admin":false},"created_at":"2016-11-11T09:07:21Z","updated_at":"2016-11-11T09:07:21Z","body":"For the right-hand side the available pyridines seem good choices. Since key question we are trying to address is \"Can we increase solubility whilst maintaining potency\" for the left hand side I'd just use a simple phenethyl ether since this would allow direct comparison with the corresponding 4-chlorophenyl and 4-CF3phenyl analogues."}}
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