2. Academic Validation
  3. Lead optimization of imidazopyrazines: a new class of antimalarial with activity on Plasmodium liver stages

Lead optimization of imidazopyrazines: a new class of antimalarial with activity on Plasmodium liver stages

  • ACS Med Chem Lett. 2014 Jul 6;5(8):947-50. doi: 10.1021/ml500244m.
Bin Zou 1,  Advait Nagle 2,  Arnab K Chatterjee 2,  Seh Yong Leong 1,  Liying Jocelyn Tan 1,  Wei Lin Sandra Sim 1,  Pranab Mishra 2,  Prasuna Guntapalli 2,  David C Tully 2,  Suresh B Lakshminarayana 1,  Chek Shik Lim 1,  Yong Cheng Tan 1,  Siti Nurdiana Abas 1,  Christophe Bodenreider 1,  Kelli L Kuhen 2,  Kerstin Gagaring 2,  Rachel Borboa 2,  Jonathan Chang 2,  Chun Li 2,  Thomas Hollenbeck 2,  Tove Tuntland 2,  Anne-Marie Zeeman 3,  Clemens H M Kocken 3,  Case McNamara 2,  Nobutaka Kato 2,  Elizabeth A Winzeler 4,  Bryan K S Yeung 1,  Thierry T Diagana 1,  Paul W Smith 1,  Jason Roland 2
Affiliations

Affiliations

  • 1 Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
  • 2 Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
  • 3 Department of Parasitology, Biomedical Primate Research Centre , 2280 GH Rijswijk, The Netherlands.
  • 4 Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States ; Department of Pediatrics, School of Medicine, University of California , San Diego, California 92093, United States.
PMID: 25147620 DOI: 10.1021/ml500244m
Abstract

Imidazopyridine 1 was identified from a phenotypic screen against P. falciparum (Pf) blood stages and subsequently optimized for activity on liver-stage schizonts of the rodent Parasite P. yoelii (Py) as well as hypnozoites of the simian Parasite P. cynomolgi (Pc). We applied these various assays to the cell-based lead optimization of the imidazopyrazines, exemplified by 3 (KAI407), and show that optimized compounds within the series with improved pharmacokinetic properties achieve causal prophylactic activity in vivo and may have the potential to target the dormant stages of P. vivax malaria.

Keywords

Liver-stage antimalarial; imidazopyrazines; lead optimization; structure−activity relationship.

Figures
Products