2-Aminopyridines were identified from phenotypic whole cell high-throughput screening of a commercially available SoftFocus kinase library as promising selective in vitro antiplasmodial hits. The selected hits were validated through re-synthesis, retesting, physico-chemical and in vitro metabolism screens and showed attractive properties for a �Hit to Lead� medicinal chemistry program. MMV017007 , was identified as a lead compound possessing good in vivo efficacy in mice Pf SCID (ED90 3.6 mg/kg) and pharmacokinetics properties in rat (F = 83% and half-life 8.7 hrs). However, MMV017007  showed potential cardiovascular risks through hERG inhibition (IC50 5.5 �M) and a high predicted human dose. MMV017007  was subjected to a lead optimization program resulting in a late Lead and pre-clinical candidate, compound MMV390048 . This pre-clinical candidate showed impressive in vitro Pf activity and overcame cardiovascular risks having low hERG inhibition (IC50 >11 �M). MMV390048  completely cured P. berghei-infected mice at low oral doses (4 x 3 mg/kg or 1 x 30 mg/kg) and ED90 of 0.57 mg/kg in Pf SCID mouse model. The data suggested that MMV390048  has potential to be a component in a single dose cure. The results from toxicological, safety, pharmacology and pharmacokinetic studies demonstrate that MMV390048  may be safely administered to humans. Phase I FIM single rising dose studies of this compound are scheduled to start in 2014.Studies using both genomics and chemoproteomic techniques that identified PfPI4K as the target of MMV390048  will be described.

Antimalarial 2-aminopyridine MMV390048 clinical candidate: Discovery and target identification studies

248th National Meeting (2014)

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