Aims, Concerns and Current Interest in Series 4

Current Series Aims

1. Lead optimisation, to improve solubility and metabolic stability while maintaining potency.
   
2. Validation of PfATP4 activity as mechanism of action via experimental and computational means.
   
3. To source more chemical and biological inputs from the widest possible community.
   

Notable Points about The Series

1. Compounds in this series have been identified down to 16 nM potency.
2. Seems to have good in vitro HLM and hHEP stability: CL_int < 8.1 is compatible with 10 nM potency.
3. RLM remains stubbornly high, particularly for the more potent analogues translating to short half-lives in rat PK. It's possible that rat metabolism may not be a good model for human metabolism for this series.
4. Series appears to have little polypharmacology or cytotoxicity.
5. There is strong correlation between activity vs. Pfal and activity in Kiaran Kirk’s ion regulation assay, implying the mechanism of action is inhibition of PfATP4.

Concerns about The Series

1. Although https://en.wikipedia.org/wiki/Dofetilide# binding looks weak or nil, the series has shown activity in a patch clamp assay at Essen (1-10 μM) which is quite potent though with a window of >100 fold over Pfal potency.
2. In Kip Guy’s resistant mutants the picture is mixed, but there is still support for the idea that some members of the series are weaker in the resistant strains. The series has no or weak >>1 μM activity against gametocytes, no activity against Winzeler’s Pb liver stage and may have weak activity against ookinetes but the dose-response data has not been completed.