Concise Minutes of the OSDD Open Meeting 17th December 2012

03 Jan
Published by Alice Williamson

+OSDD Malaria, @OSDDMalaria
Matthew Houghton Todd (MHT), University of Sydney, +Matthew Todd, @MatToddChem; Paul Willis (PW), Medicines for Malaria Venture,; Murray N Robertson (MNR), University of Sydney, +Murray Robertson, @murrayfold; Alice E Williamson (AEW), University of Sydney, +Alice Williamson, @all_isee; Jimmy R Cronshaw (JRC), University of Sydney, + Jimmy Cronshaw, @JimCronshaw; Kat Badiola (KB), University of Sydney, + Katrina Badiola, @CaverKat; Angela Butera (AB), University of Sydney; Chris Southan (CS), ChrisDS Consulting Limited, +Christopher Southan, @cdsouthan; Ginger Taylor (GT), The Synaptic Leap; Girinath G Pillai (GGP), University of Florida, +Girinath G. Pillai, @giribio; Hong Shen (HS), Roche; Jen Wike (JW),, +Jen Wike, @JenWike; Mike Gretes (MG), Oregon State University, +Mike Gretes; Mike Pollastri (MP), Northeastern University, @NUTrypKiller; Patrick Thomson (PT), +Patrick Thomson, @patrickthomson
Sanjay Batra (SB), Central Drug Research Institute, +Sanjay Batra; Matin Dean (MD), University of Sydney, +Matin Dean
Welcome and Project Background (MHT)
See Agenda and Abridged Transcript for more information.
MHT Outlined three important questions to be answered in this meeting:
• Do we continue with some more compounds of aryl pyrrole series?
• What does modelling data (MNR) suggest?
• Should we revisit the ‘near-neighbours’?
• Do we continue with some more compounds of aryl pyrrole series?
MHT We still need to synthesise the three 'Most Wanted' compounds identified from the consultation, have proved synthetically challenging to date.

PW Thinks we should use the pharmacophore model (developed by MNR) to prioritise the 'most wanted' compounds as little point in investing more synthetic effort into compounds likely to be inactive.
MHT Agrees but also thinks we need the compounds for publication. Mentions the possibility of paying a CRO to make the ether, MD and new project member PT are working on sulfonamide and AEW will continue work on oxadiazole. Sydney team have performed search of TCAMS set and found other active compounds containing aryl pyrrole. Based on this search and considering active compounds (OSM-S-5 and OSM-S-6) the Sydney team propose another set of target compounds.

PW Suggests we check if fragments A and B have been tested already. If not, and they are commercial or easy to make then go ahead. For esters C and D less enthusiasm as the ester is the stumbling block (low metabolic stability) and will need to be replaced even if the compounds are active. Thinks looks complicate and so also not worth a long programme of synthesis.
MHT Questions whether we are unfairly critising the ester as although its unstable in mouse plasma, seems to be stable in human plasma according to experiments conducted to date.
PW Possibly, but as safety tests are performed in rodent models during latter stages of drug-development its important for the early compounds to be stable in mouse models.
• What does modelling data (MNR) suggest?
MHT All compounds where the ester has been replaced or removed have been less active. MNR has done some preliminary modellling suggesting that ester is important.
MNR Yes, data so far suggests ester or isostere required for activity. Will perform more modelling with collaboration from other group recruited on Twitter.
• Should we revisit the ‘near-neighbours’?
MHT Particularly interested that 'near-neighbours fit the modelling results despite lack of ester.
MNR Seems that one carbonyl overlaps and sulfur atom acts as a hydrogen bond acceptor.
MHT Should we revisit this series - highly active and no ester. So far, red flag of Michael acceptor properties doesn't seem so reactive - will test this in Sue Charman's lab. Asks PW if he is solidly against this series (particularly due to activity in late stage gametocyte assay-distinguishing feature between this set and the aryl pyrroles)?
PW Troubled by ligand efficiency. Much larger MW than aryl pyrroles which are also active.
MHT Suggests we modify OSM-S-35, smallest MW of 'near-neighbours'.

PW Need to think of related structures that are more drug-like to improve oral activity. But not necessary to completely steer clear of near-neighbour core.
MHT  Suggests options if moving away from aryl pyrroles:

  • Tweak the 'near-neighbours'
  • Look at one of the hybrid compounds
  • Triazoloureas (OSM-S-56) or is another group interested?

  • Thienopyrimidines - original hit now synthesised and ready for testing, JRC will synthesise a small library in Jan
  • Pick new series but need to consult with MMV and GSK to prevent duplication of efforts

PW Suggests we pick some possible targets from TCAMS data set or Malaria box and discuss/decide a new series in the next meeting.
MHT Agrees and says team will concentrate on 'near-neighbours', thienopyrimidines and the sulphonamide. Meeting planned for mid-Feb, tba.
MHT Can we use modelling to predict the target?
MNR In theory if we screen with kinase panel data and look for trends
MHT Could we look for compounds with DHODH (dihydroorotate dehydrogenase) activity and map them?
PW Interesting but not helpful for early lead criteria, could run on the side.
CS Offers to do work to identify assays and people working on these. Ask about importance/advantage of knowing target of action.
PW Target ID not so important for drug development.
MNR Asks about potential of purchasing small library of commerical compounds that fit pharmacophore model.
PW Agrees to online shortlist and discussion.