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

Claire Le Manach; Tanya Paquet; Christel Brunschwig; Mathew Njoroge; Ze Han; Diego Gonzàlez Cabrera; Sridevi Bashyam; Rajkumar Dhinakaran; Dale Taylor; Janette Reader; Mariette Botha; Alisje Churchyard; Sonja Lauterbach; Theresa L Coetzer; Lyn-Marie Birkholtz; Stephan Meister; Elizabeth A Winzeler; David Waterson; Michael J Witty; Sergio Wittlin; María-Belén Jiménez-Díaz; María Santos Martínez; Santiago Ferrer; Iñigo Angulo-Barturen; Leslie J Street; Kelly Chibale

doi:10.1021/acs.jmedchem.5b01605

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

J Med Chem. 2015 Nov 12;58(21):8713-22. doi: 10.1021/acs.jmedchem.5b01605. Epub 2015 Nov 2.

Authors

Claire Le Manach, Tanya Paquet, Christel Brunschwig¹, Mathew Njoroge¹, Ze Han, Diego Gonzàlez Cabrera, Sridevi Bashyam², Rajkumar Dhinakaran², Dale Taylor¹, Janette Reader³, Mariette Botha³, Alisje Churchyard³, Sonja Lauterbach³, Theresa L Coetzer⁴, Lyn-Marie Birkholtz³, Stephan Meister⁵, Elizabeth A Winzeler⁵, David Waterson⁶, Michael J Witty⁶, Sergio Wittlin^{7

8}, María-Belén Jiménez-Díaz⁹, María Santos Martínez⁹, Santiago Ferrer⁹, Iñigo Angulo-Barturen⁹, Leslie J Street, Kelly Chibale

Affiliations

¹ Division of Clinical Pharmacology, Department of Medicine, University of Cape Town , Observatory 7925, South Africa.
² Syngene International Ltd. , Biocon Park, Plot No. 2 & 3, Bommasandra IV Phase, Jigani Link Road, Bangalore 560099, India.
³ Department of Biochemistry, Centre for Sustainable Malaria Control, University of Pretoria , Private bag X20, Hatfield 0028, South Africa.
⁴ Department of Molecular Medicine and Haematology, Wits Research Institute for Malaria, Wits Medical School , 2000 Johannesburg, South Africa.
⁵ School of Medicine, Department of Pediatrics, Pharmacology & Drug Discovery, University of California, San Diego (UCSD) , 9500 Gilman Drive, La Jolla, California 92093, United States.
⁶ Medicines for Malaria Venture , ICC, Route de Pré-Bois 20, PO Box 1826, 1215 Geneva, Switzerland.
⁷ Swiss Tropical and Public Health Institute , Socinstrasse 57, 4002 Basel, Switzerland.
⁸ University of Basel , 4003 Basel, Switzerland.
⁹ GlaxoSmithKline , Tres Cantos Medicines Development Campus, Severo Ochoa, 2, 28760 Tres Cantos, Madrid, Spain.

PMID: 26502160
DOI: 10.1021/acs.jmedchem.5b01605

Abstract

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Antimalarials / chemistry*
Antimalarials / pharmacokinetics
Antimalarials / pharmacology
Antimalarials / therapeutic use*
Ether-A-Go-Go Potassium Channels / metabolism
Humans
Liver / parasitology
Malaria / drug therapy*
Malaria / parasitology
Malaria, Falciparum / drug therapy
Malaria, Falciparum / parasitology
Mice
Plasmodium berghei / drug effects*
Plasmodium falciparum / drug effects*
Pyrazoles / chemistry*
Pyrazoles / pharmacokinetics
Pyrazoles / pharmacology
Pyrazoles / therapeutic use*
Pyridines / chemistry*
Pyridines / pharmacokinetics
Pyridines / pharmacology
Pyridines / therapeutic use*
Rats
Structure-Activity Relationship

Substances

Antimalarials
Ether-A-Go-Go Potassium Channels
Pyrazoles
Pyridines
pyrazolopyridine