Vortrag (Online-Veranstaltung)
Design of Potent and Orally Available Antimalarial PMX Inhibitors via Molecular Property Optimization
Dr. Teresa de Haro
UCB
Malaria is a serious mosquito-borne disease with an estimated 249 million cases and 608,000 deaths worldwide in 2022, predominantly in small children in Africa.(1) There is a constant need for novel antimalarial medicines to complement existing artemisinin-dependent therapies, which are under pressure from resistance conferring mutations. Plasmepsin X (PMX), an essential aspartyl protease of malaria parasite, has been identified as new potential multistage drug target to fight against malaria. PMX controls malaria parasite egress and invasion of erythrocytes, development of functional liver merozoites (prophylactic activity) and blocking transmission to mosquitoes.(2) UCB in collaboration with Medicines for Malaria Venture (MMV) identified UCB7362, a potent, orally available, PMX inhibitor with in vivo antimalaria activity. However, preclinical assessment of UCB7362, revealed a suboptimal dose paradigm (once daily dosing of 50 mg for 7 days for treatment of uncomplicated malaria) relative to current standard of care (three-dose regime).(3) Molecular property optimization to balance potency, selectivity, and pharmacokinetic parameters led to the identification of a biaryl chemical series with increased metabolic stability, higher Vss and accordingly longer t½ than UCB7362 while maintaining the off-target hit rate of UCB7362.(4)
(1) WHO. World Malaria Report 2023. Word Health Organization, Geneva, 2023, ISBN 978-92-4-008617-3
(2) a) Pino P, Caldelari R, Mukherjee B, Vahokoski J, Klages N, Maco B, Collins CR, Blackman MJ, Kursula I, Heussler V, Brochet M, Soldati-Favre D. Science. 2017, 358, 522-528. b) Nasamu AS, Glushakova S, Russo I, Vaupel B, Oksman A, Kim AS, Fremont DH, Tolia N, Beck JR, Meyers MJ, Niles JC, Zimmerberg J, Goldberg DE. Science, 2017, 358, 518-522.
(3) Lowe MA, Cardenas A, Valentin JP, Zhu Z, Abendroth J, Castro JL, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer DD, MacCoss M, Rowley JH, Rosseels ML, Royer L, Taylor RD, Wong M, Zaccheo O, Chavan VP, Ghule GA, Tapkir BK, Burrows JN, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jiménez-Díaz MB, Striepen J, Fairhurst KJ, Yeo T, Fidock DA, Cowman AF, Favuzza P, Crespo-Fernandez B, Gamo FJ, Goldberg DE, Soldati-Favre D, Laleu B, de Haro T. J. Med.Chem 2022, 65,14121-14143
(4) Sakata K, Lowe MA, Xuan M, Bruffaerts J, Stasi LP, Lallemand B, Cardenas A, Taylor RD, Vidler LR, King L, Valentin JP, Laleu B, de Haro T. ACS Med Chem Lett. 2023, 14, :1582-1588
(1) WHO. World Malaria Report 2023. Word Health Organization, Geneva, 2023, ISBN 978-92-4-008617-3
(2) a) Pino P, Caldelari R, Mukherjee B, Vahokoski J, Klages N, Maco B, Collins CR, Blackman MJ, Kursula I, Heussler V, Brochet M, Soldati-Favre D. Science. 2017, 358, 522-528. b) Nasamu AS, Glushakova S, Russo I, Vaupel B, Oksman A, Kim AS, Fremont DH, Tolia N, Beck JR, Meyers MJ, Niles JC, Zimmerberg J, Goldberg DE. Science, 2017, 358, 518-522.
(3) Lowe MA, Cardenas A, Valentin JP, Zhu Z, Abendroth J, Castro JL, Class R, Delaunois A, Fleurance R, Gerets H, Gryshkova V, King L, Lorimer DD, MacCoss M, Rowley JH, Rosseels ML, Royer L, Taylor RD, Wong M, Zaccheo O, Chavan VP, Ghule GA, Tapkir BK, Burrows JN, Duffey M, Rottmann M, Wittlin S, Angulo-Barturen I, Jiménez-Díaz MB, Striepen J, Fairhurst KJ, Yeo T, Fidock DA, Cowman AF, Favuzza P, Crespo-Fernandez B, Gamo FJ, Goldberg DE, Soldati-Favre D, Laleu B, de Haro T. J. Med.Chem 2022, 65,14121-14143
(4) Sakata K, Lowe MA, Xuan M, Bruffaerts J, Stasi LP, Lallemand B, Cardenas A, Taylor RD, Vidler LR, King L, Valentin JP, Laleu B, de Haro T. ACS Med Chem Lett. 2023, 14, :1582-1588