Malaria is a major global disease caused by parasites of the genus Plasmodium, which are transmitted to people when infected female anopheles mosquitoes feed on human blood. According to the last World Health Organization (WHO) Malaria report, in 2016 there were an estimated of 216 million cases with approximately 445,000 deaths worldwide. Among the different Plasmodium species that infects humans, falciparum is accountable for nearly 90% of these deaths and children under 5 are particularly susceptible to malaria illness, infection and death. In addition, malaria has a severe socioeconomic impact in countries where it is endemic because of the persistent and disabling symptoms of the disease. Approximately 25% of the endemic countries incomes are devoted to treating and minimizing the impact of this disease. In the African continent alone the economic burden is estimated at $12 billion annually. A current area of global concern in malaria is the emergence of resistance to antimalarial drugs, including the artemisinins (current gold standard treatment). As a consequence, there is an urgent requirement for novel antimalarial drugs with novel mechanism of action that can be deployed to treat the disease. Pyrrolidinamides has emerged as a novel potent antimalarial chemical class with activity against resistant strains and potential to deliver a safe, oral new antimalarial medicine. In this session, we will disclose for the first time the structure of GSK701, the first antimalarial clinical candidate belonging to this chemical class. GSK701 is the result of a collaboration between GSK and the Wellcome Trust focused on developing this chemical class discovered from a phenotypic screening of the GSK collection. GSK701 has a physicochemical and safety profile appropriate for oral administration, a robust multi-gram synthetic route and is predicted to be effective against P. falciparum malaria with a low dose. The medicinal chemistry strategy, SAR, clinical plans and results of the target identification strategy will be discussed during this presentation.

Discovery of pyrrolidinamides, a novel chemical class for malaria treatment: First time disclosure of the orally bioavailable clinical candidate GSK701

256th National Meeting (2018)

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