Discovery of a Pyrazine-2-Carboxamide Derivative as a Potent Plasmodium falciparum Inhibitor with Potential for Single-Dose Cure
Vanessa M. Marx, Anne-Catherine Mata, Fumiaki Yokokawa, Thomas Kirrane, Richard Huang, Suresh B. Lakshminarayana, Jay Prakash Jain, Judith Straimer, W. Armand Guiguemde, Luying Pei, Upendra Kulkarni, Christopher J. Thompson, Johanna M. Jansen, Patrick S. Lee, Eric J. Martin, Valery R. Polyakov, Nicole Blaquiere, Alexander Burckle, Grace Waldron, Benjamin R. Taft, Erika L. Flannery, Hanna Schulz, Qumber H. Jafri, Katherine Chan, Erika Kim, Harry Cheung, Vida Ahyong, Changbok Lee, Catherine L. Jones, Christopher S. Lunde, Iñigo Angulo-Barturen, María Belén Jiménez-Díaz, Leyre Pernaute-Lau, Christian Scheurer, Sibylle Sax, Sergio Wittlin, Anna Caroline Campos Aguiar, Rafael Victorio Carvalho Guido, Dhelio B. Pereira, Philip J. Rosenthal, Roland A. Cooper, Kyra A. Schindler, David A. Fidock, Brice Campo, Simon F. Campbell, Thierry T. Diagana, Christopher R. SarkoAbstract
Malaria remains a major cause of morbidity and mortality, particularly among young children, in endemic regions such as sub-Saharan Africa and Southeast Asia. Moreover, the emerging resistance of Plasmodium parasites to front-line therapeutics underscores the need for new blood-stage antimalarial drugs. Utilizing a Plasmodium falciparum (Pf) growth inhibition assay, we identified a novel pyrazine-2-carboxamide series. Lead optimization improved anti-plasmodial potency, metabolic stability, and reduced CYP2D6 inhibition risk, leading to the selection of IWY357 (1). A single dose of 100 mg per kg (mpk) is fully curative in a Pf-humanized severe combined immunodeficient mouse model (TADhuMouse®-Pfalc), and IWY357 (1) also exhibits a high barrier to resistance in drug selection studies. Given the significant potential to provide a curative therapy for uncomplicated malaria with short dosing regimens, either alone or in combination, IWY357 (1) was progressed through GLP toxicology studies into phase 1 clinical trials.