A Novel Pyrazolopyridine with in Vivo Activity in Plasmodium berghei- and Plasmodium falciparum-Infected Mouse Models from Structure-Activity Relationship Studies around the Core of Recently Identified Antimalarial Imidazopyridazines.
Toward improving pharmacokinetics, in vivo efficacy, and selectivity over hERG, structure-activity relationship studies around the central core of antimalarial imidazopyridazines were conducted. This study led to the identification of potent pyrazolopyridines, which showed good in vivo efficacy and pharmacokinetics profiles. The lead compounds also proved to be very potent in the parasite liver and gametocyte stages, which makes them of high interest.
Claire
C
Le Manach
Tanya
T
Paquet
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory 7925, South Africa.
Christel
C
Brunschwig
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory 7925, South Africa.
Mathew
M
Njoroge
Ze
Z
Han
Diego
D
Gonzàlez Cabrera
Syngene International Ltd. , Biocon Park, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
Sridevi
S
Bashyam
Syngene International Ltd. , Biocon Park, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
Rajkumar
R
Dhinakaran
Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory 7925, South Africa.
Dale
D
Taylor
Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private bag X20, Hatfield 0028, South Africa.
Janette
J
Reader
Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private bag X20, Hatfield 0028, South Africa.
Mariette
M
Botha
Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private bag X20, Hatfield 0028, South Africa.
Alisje
A
Churchyard
Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private bag X20, Hatfield 0028, South Africa.
Sonja
S
Lauterbach
Department of Molecular Medicine and Haematology, Wits Research Institute for Malaria, Wits Medical School , 2000 Johannesburg, South Africa.
Theresa L
TL
Coetzer
Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private bag X20, Hatfield 0028, South Africa.
Lyn-Marie
LM
Birkholtz
School of Medicine, Department of Pediatrics, Pharmacology & Drug Discovery, University of California, San Diego (UCSD) , 9500 Gilman Drive, La Jolla, California 92093, United States.
Stephan
S
Meister
School of Medicine, Department of Pediatrics, Pharmacology & Drug Discovery, University of California, San Diego (UCSD) , 9500 Gilman Drive, La Jolla, California 92093, United States.
Elizabeth A
EA
Winzeler
Medicines for Malaria Venture , ICC, Route de Pré-Bois 20, PO Box 1826, 1215 Geneva, Switzerland.
David
D
Waterson
Medicines for Malaria Venture , ICC, Route de Pré-Bois 20, PO Box 1826, 1215 Geneva, Switzerland.
Michael J
MJ
Witty
Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.|University of Basel , 4003 Basel, Switzerland.
Sergio
S
Wittlin
GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
María-Belén
MB
Jiménez-Díaz
GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
María
M
Santos Martínez
GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
Santiago
S
Ferrer
GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.
Iñigo
I
Angulo-Barturen
Leslie J
LJ
Street
Kelly
K
Chibale
D000818:Animals; D000962:Antimalarials / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051638:Ether-A-Go-Go Potassium Channels / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000469:parasitology; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D010962:Plasmodium berghei / Q000187:drug effects*; D010963:Plasmodium falciparum / Q000187:drug effects*; D011720:Pyrazoles / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D013329:Structure-Activity Relationship
D000962:Antimalarials; D051638:Ether-A-Go-Go Potassium Channels; D011720:Pyrazoles; D011725:Pyridines; C118531:pyrazolopyridine