title: Lead optimization of imidazopyrazines: a new class of antimalarial with activity on Plasmodium liver stages.
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.
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Bin
authors.initials: B
authors.lastname: Zou
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Seh Yong
authors.initials: SY
authors.lastname: Leong
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Liying Jocelyn
authors.initials: LJ
authors.lastname: Tan
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Wei Lin Sandra
authors.initials: WL
authors.lastname: Sim
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Pranab
authors.initials: P
authors.lastname: Mishra
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Prasuna
authors.initials: P
authors.lastname: Guntapalli
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: David C
authors.initials: DC
authors.lastname: Tully
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Chek Shik
authors.initials: CS
authors.lastname: Lim
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Yong Cheng
authors.initials: YC
authors.lastname: Tan
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Siti Nurdiana
authors.initials: SN
authors.lastname: Abas
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Christophe
authors.initials: C
authors.lastname: Bodenreider
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Kelli L
authors.initials: KL
authors.lastname: Kuhen
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gagaring
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Rachel
authors.initials: R
authors.lastname: Borboa
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chang
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Thomas
authors.initials: T
authors.lastname: Hollenbeck
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.affiliation: Department of Parasitology, Biomedical Primate Research Centre , 2280 GH Rijswijk, The Netherlands.
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Zeeman
authors.affiliation: Department of Parasitology, Biomedical Primate Research Centre , 2280 GH Rijswijk, The Netherlands.
authors.forename: Clemens H M
authors.initials: CH
authors.lastname: Kocken
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Case
authors.initials: C
authors.lastname: McNamara
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Kato
authors.affiliation: 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.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Bryan K S
authors.initials: BK
authors.lastname: Yeung
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
authors.affiliation: Novartis Institute for Tropical Diseases , 10 Biopolis Road #05-01 Chromos, 138670 Singapore.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
authors.affiliation: Genomics Institute of the Novartis Research Foundation , San Diego, California 92121, United States.
authors.forename: Jason
authors.initials: J
authors.lastname: Roland
keywords: Liver-stage antimalarial; imidazopyrazines; lead optimization; structure−activity relationship