title: Imidazolopiperazines: lead optimization of the second-generation antimalarial agents.
abstract: On the basis of the initial success of optimization of a novel series of imidazolopiperazines, a second generation of compounds involving changes in the core piperazine ring was synthesized to improve antimalarial properties. These changes were carried out to further improve the potency and metabolic stability of the compounds by leveraging the outcome of a set of in vitro metabolic identification studies. The optimized 8,8-dimethyl imidazolopiperazine analogues exhibited improved potency, in vitro metabolic stability profile and, as a result, enhanced oral exposure in vivo in mice. The optimized compounds were found to be more efficacious than the current antimalarials in a malaria mouse model. They exhibit moderate oral exposure in rat pharmacokinetic studies to achieve sufficient multiples of the oral exposure at the efficacious dose in toxicology studies.
authors.affiliation: Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, San Diego, California 92121, USA.
authors.forename: Advait
authors.initials: A
authors.lastname: Nagle
authors.forename: Tao
authors.initials: T
authors.lastname: Wu
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.forename: Kerstin
authors.initials: K
authors.lastname: Gagaring
authors.forename: Rachel
authors.initials: R
authors.lastname: Borboa
authors.forename: Caroline
authors.initials: C
authors.lastname: Francek
authors.forename: Zhong
authors.initials: Z
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Plouffe
authors.forename: Xuena
authors.initials: X
authors.lastname: Lin
authors.forename: Christopher
authors.initials: C
authors.lastname: Caldwell
authors.forename: Jared
authors.initials: J
authors.lastname: Ek
authors.forename: Suzanne
authors.initials: S
authors.lastname: Skolnik
authors.forename: Fenghua
authors.initials: F
authors.lastname: Liu
authors.forename: Jianling
authors.initials: J
authors.lastname: Wang
authors.forename: Jonathan
authors.initials: J
authors.lastname: Chang
authors.forename: Chun
authors.initials: C
authors.lastname: Li
authors.forename: Bo
authors.initials: B
authors.lastname: Liu
authors.forename: Thomas
authors.initials: T
authors.lastname: Hollenbeck
authors.forename: Tove
authors.initials: T
authors.lastname: Tuntland
authors.forename: John
authors.initials: J
authors.lastname: Isbell
authors.forename: Tiffany
authors.initials: T
authors.lastname: Chuan
authors.forename: Philip B
authors.initials: PB
authors.lastname: Alper
authors.forename: Christoph
authors.initials: C
authors.lastname: Fischli
authors.forename: Reto
authors.initials: R
authors.lastname: Brun
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.forename: Matthias
authors.initials: M
authors.lastname: Rottmann
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Winzeler
authors.forename: Richard
authors.initials: R
authors.lastname: Glynne
authors.forename: David C
authors.initials: DC
authors.lastname: Tully
authors.forename: Arnab K
authors.initials: AK
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001682:Biological Availability; D018938:Caco-2 Cells; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D016778:Malaria, Falciparum / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D010879:Piperazines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship
chemical_list: D000962:Antimalarials; D007093:Imidazoles; D010879:Piperazines