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Draft Agenda for OSDD Consultation:
The next meeting will take place online at this location: Meeting Room
At these times Monday 17th December 2012:
San Francisco 6 am
New York 9 am
London 2 pm
Geneva 3 pm
Delhi 7:30 pm
Sydney 1 am (so on Tuesday 18th)
Agenda Items: (being edited)
1. Summary of current aryl pyrrole status and biological results
Detailed agenda/summary: (many links + backstory in The Story So Far)
First Round: Data and discussion: see here Includes: confirmation of activity of TCMDC-123812 (OSM-S-5) and TCMDC-123794 (OSM-S-6), exploration of prodrug hypothesis and identification of first near neighbor as active (OSM-S-9).
Second Round: Data and discussion: see here Simple ester-to-amide replacements eliminated activity. Near neighbor set continued to perform well, though strong logP-to-potency correlation. Sanjay's 3-F near neighbor analog was inactive, implying strong effect of arylpyrrole substituents too.
a) Metabolism: Phosphate buffer: see here - GSK originals (OSM-S-5 and OSM-S-6) degraded faster than the less soluble near neighbors. Plasma analysis: see here GSK compound OSM-S-5 metabolized in mouse plasma, but stable in human.
b) hERG: see here GSK compound OSM-S-5 passed, as did a potent near neighbor compound (OSM-S-35). Taken as representative for series.
c) Late Stage Gametocyte assays: see here original GSK (no) and 3 near neighbors (potent).
d) In vivo: see here No oral efficacy. PK data: see here and here Clear decrease in plasma levels over time in mouse, supporting idea that compounds are available but metabolised/cleared Summary of some aspects of this biology: see here
Third round: Predicated in increasing metabolic stability of original GSK compounds, and shelving near neighbor set due to solubility problems. Consultation, resulting in commercial and synthetic Top-10 lists.
Biological Data from Third Round:
part 1: (Oct 19th): see here Amide/amine replacements for ester in OSM-S-5 eliminate activity. Pyrazole eliminates activity. Matin's gem-dimethyl eliminates activity.
part 2: (Nov 8): see here Many amide replacements inactive. Dimethylpyrrole replaced by pyrazole inactive. A few non-ester compounds were found to possess some activity, however.
part 3: (Dec 10): see here Ketone replacement of ester (OSM-S-102/103) not great, but methylation of primary amide again found to be poor.
2. Recent summary of the biological data: see here and here
3. Where things stand on remaining compounds needed: see here
4. Analyses of the data already posted elsewhere:
Previous discussion of these data, highlighting trends.
Importance of primary amide side chain.
Impact of replacing ester with amides and amines. And impact on the two original GSK compounds.
Dramatic impact of methylation of the hit compound.
Low efficacy of pyrazoles.
Prodrug hypothesis II and III
Reminder of the efficacy of the near neighbour thiazolidinones.
Suggestion of next compounds, including hybrids, and the WANTED! compounds.
5. Questions arising:
1) Is it worth making more compounds in this series, if so which?
2) Should we revisit near neighbor set with view to increasing solubility?
3) Is it just accidental that the near neighbor set are potent, or are these compounds all essentially hitting the same target. Is the ester important because of the geometry it imparts, rather than as a functional group itself?
4) General/minor: Are the compounds cytotoxic? (Related to the above) Discuss modelling results and the proposed 'new' arylpyrrole substrates for synthesis. Discuss the results for Jimmy's compounds and which thienopyrimidines and triazolourea to synthesise next. Discuss ways to increase participation in project , e.g. teams that might be interested in contributing molecules, or upcoming meetings where project could be presented. A.O.B and reminder of items carried over from last meeting (e.g. website redesign) Date of next meeting