Optimization of an imidazopyridazine series of inhibitors of plasmodium falciparum calcium-dependent protein kinase 1 (Pf CDPK1)

Journal of Medicinal Chemistry

Volumn 57, Issue 8, 2014, Pages 3570-3587

  Chapman, Timothy M ^a   Osborne, Simon A ^a   Wallace, Claire ^a   Birchall, Kristian ^a   Bouloc, Nathalie ^a   Jones, Hayley M ^a   Ansell, Keith H ^a   Taylor, Debra L ^a   Clough, Barbara ^b   Green, Judith L ^b   Holder, Anthony A ^b  

^a MEDICAL RESEARCH COUNCIL   (United Kingdom)

^b NATIONAL INSTITUTE FOR MEDICAL RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

3 [2 [(3 FLUOROPYRIDIN 2 YL)AMINO]PYRIMIDIN 5 YL] N (1 METHYLPIPERIDIN 4 YL)IMIDAZO[1,2 B]PYRIDAZIN 6 AMINE; 3 [2 [(3 FLUOROPYRIDIN 2 YL)AMINO]PYRIMIDIN 5 YL] N (PYRROLIDIN 3 YL)IMIDAZO[1,2 B]PYRIDAZIN 6 AMINE; 3 [6 [(3 FLUOROPYRIDIN 2 YL)AMINO]PYRIDIN 3 YL] N (PIPERIDIN 4 YL)IMIDAZO[1,2 B]PYRIDAZIN 6 AMINE; ANTIMALARIAL AGENT; CHLOROQUINE; ENZYME INHIBITOR; IMIDAZOLE DERIVATIVE; N (3 FLUOROPYRIDIN 2 YL) 5 (6 METHYLIMIDAZO[1,2 B]PYRIDAZIN 3 YL)PYRIMIDIN 2 AMINE; N (3 FLUOROPYRIDIN 2 YL) 5 [6 (PIPERAZIN 1 YL)IMIDAZO[1,2 B]PYRIDAZIN 3 YL]PYRIMIDIN 2 AMINE; N (3 FLUOROPYRIDIN 3 YL) 5 [6 (4 METHYLPIPERAZIN 1 YL)IMIDAZO[1,2 B]PYRIDAZIN 3 YL]PYRIMIDIN 2 AMINE; N [3 [2 (PHENYLAMINO)PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]CYCLOHEXANE 1,4 DIAMINE; N [3 [2 (PYRAZIN 2 YLAMINO)PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]CYCLOHEXANE 1,4 DIAMINE; N [3 [2 (PYRIDIN 2 YLAMINO)PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]CYCLOHEXANE 1,4 DIAMINE; N [3 [2 (PYRIDIN 3 YLAMINO)PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]CYCLOHEXANE 1,4 DIAMINE; N [3 [2 (PYRIMIDIN 2 YLAMINO)PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]CYCLOHEXANE 1,4 DIAMINE; N [3 [2 [(3 FLUOROPYRIDIN 2 YL)AMINO]PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]CYCLOHEXANE 1,4 DIAMINE; N [3 [2 [(5 METHYLPYRIDIN 2 YL)AMINO]PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]CYCLOHEXANE 1,4 DIAMINE; N [3 [2 [(PYRIDIN 2 YLMETHYL)AMINO]PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]CYCLOHEXANE 1,4 DIAMINE; N [3 [2 [(PYRIDIN 3 YLMETHYL)AMINO]PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]CYCLOHEXANE 1,4 DIAMINE; N [3 [2 [[(1 METHYL 1H PYRAZOL 3 YL)METHYL]AMINO]PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]CYCLOHEXANE 1,4 DIAMINE; N [3 [2 [[3 FLUORO 5(TRIFLUOROMETHYL)PYRIDIN 2 YL]AMINO]PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]CYCLOHEXANE 1,4 DIAMINE; PLASMODIUM FALCIPARUM CALCIUM DEPENDENT PROTEIN KINASE 1 INHIBITOR; PYRIDAZINE DERIVATIVE; TERT BUTYL 4 [(3 BROMOIMIDAZO[1,2 B]PYRIDAZIN 6 YL)AMINO]PIPERIDINE 1 CARBOXYLATE; TERT BUTYL 4 [[3 (2 AMINOPYRIMIDIN 5 YL)IMIDAZO[1,2 B]PYRIDAZIN 6 YL]AMINO]PIPERIDINE 1 CARBOXYLATE; TERT BUTYL 4 [[3 (6 AMINOPYRIDIN 3 YL)IMIDAZO[1,2 B]PYRIDAZIN 6 YL]AMINO]PIPERIDINE 1 CARBOXYLATE; TERT BUTYL [4 [(3 BROMOIMIDAZO[1,2 B]PYRIDAZIN 6 YL) AMINO]CYCLOHEXYL]CARBAMATE; TERT BUTYL [4 [[3 (2 AMINOPYRIMIDIN 5 YL)MIDAZO[1,2 B]PYRIDAZIN 6 YL] AMINO]CYCLOHEXYL]CARBAMATE; TERT BUTYL [4 [[3 [2 (METHYLSULFANYL)PYRIMIDIN 5 YL]IMIDAZO[1,2 B]PYRIDAZIN 6 YL]AMINO]CYCLOHEXYL]CARBAMATE; UNCLASSIFIED DRUG; UNINDEXED DRUG;

AMINO ACID SEQUENCE; ANIMAL EXPERIMENT; ANIMAL MODEL; ARTICLE; CONTROLLED STUDY; CRYSTAL STRUCTURE; CYCLIZATION; DENATURATION; DRUG ADSORPTION; DRUG BIOAVAILABILITY; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG EXCRETION; DRUG METABOLISM; DRUG STRUCTURE; ENZYME INHIBITION; FEMALE; HYDROGEN BOND; MALARIA; MOLECULAR DOCKING; MOUSE; NONHUMAN; NUCLEOPHILICITY; PARASITEMIA; PLASMODIUM BERGHEI; PLASMODIUM BERGHEI INFECTION; PLASMODIUM FALCIPARUM; SINGLE DRUG DOSE; STRUCTURE ACTIVITY RELATION; SUZUKI REACTION;

ANIMALS; ANTIMALARIALS; MICE; PLASMODIUM FALCIPARUM; PROTEIN KINASE INHIBITORS; PROTEIN KINASES; PROTOZOAN PROTEINS; PYRIDAZINES; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 84899556346     PISSN: 00222623     EISSN: 15204804     Source Type: Journal    
DOI: 10.1021/jm500342d     Document Type: Article

References (26)

1. World Malaria Report, 2010; World Health Organization. www.who.int/malaria/publications/atoz/9789241564106/en/index.html.
2. Petersen, I.; Eastman, R.; Lanzer, M. Drug-resistant malaria: molecular mechanisms and implications for public health FEBS Lett. 2011, 1551-1562
3. Harper, J. F.; Harmon, A. Plants, symbiosis and parasites: a calcium signalling connection Nat. Rev. Mol. Cell. Biol. 2005, 6, 555-566
4. Ward, P.; Equinet, L.; Packer, J.; Doerig, C. Protein kinases of the human malaria parasite Plasmodium falciparum: the kinome of a divergent eukaryote BMC Genomics 2004, 5, 79
5. Zhao, Y.; Kappes, B.; Franklin, R. M. Gene structure and expression of an unusual protein kinase from Plasmodium falciparum homologous at its carboxyl terminus with the EF hand calcium-binding proteins J. Biol. Chem. 1993, 268, 4347-4354
6. Tewari, R.; Straschil, U.; Bateman, A.; Böhme, U.; Cherevach, I.; Gong, P.; Pain, A.; Billker, O. The systematic functional analysis of Plasmodium protein kinases identifies essential regulators of mosquito transmission Cell Host Microbe 2010, 8, 377-387
7. Kato, N.; Sakata, T.; Breton, G.; Le Roch, K. G.; Nagle, A.; Andersen, C.; Bursulaya, B.; Henson, K.; Johnson, J.; Kumar, K. A.; Marr, F.; Mason, D.; McNamara, C.; Plouffe, D.; Ramachandran, V.; Spooner, M.; Tuntland, T.; Zhou, Y.; Peters, E. C.; Chatterjee, A.; Schultz, P. G.; Ward, G. E.; Gray, N.; Harper, J.; Winzeler, E. A. Gene expression and small-molecule compounds link a protein kinase to Plasmodium falciparum motility Nat. Chem. Biol. 2008, 4, 347-356
8. Green, J. L.; Rees-Channer, R. R.; Howell, S. A.; Martin, S. R.; Knuepfer, E.; Taylor, H. M.; Grainger, M.; Holder, A. A. The motor complex of Plasmodium falciparum: phosphorylation by a calcium-dependent protein kinase J. Biol. Chem. 2008, 283, 30980-30989
9. Holder, A. A.; Mohd Ridzuan, M. A.; Green, J. L. Calcium dependent protein kinase 1 and calcium fluxes in the malaria parasite Microbes Infect. 2012, 14, 825-830
10. Sebastian, S.; Brochet, M.; Collins, M. O.; Schwach, F.; Jones, M. L.; Goulding, D.; Rayner, J. C.; Choudhary, J. S.; Billker, O. A Plasmodium calcium-dependent protein kinase controls zygote development and transmission by translationally activating repressed mRNAs Cell Host Microbe 2012, 12, 9-19
11. Azevedo, M. F.; Sanders, P. R.; Krejany, E.; Nie, C. Q.; Fu, P.; Bach, L. A.; Wunderlich, G.; Crabb, B. S.; Gilson, P. R. Inhibition of Plasmodium falciparum CDPK1 by conditional expression of its J-domain demonstrates a key role in schizont development Biochem. J. 2013, 452, 433-441
12. Kugelstadt, D.; Derrer, B.; Kappes, B. Calcium-Dependent Protein Kinases as Drug Targets. In Drug Discovery in Infectious Diseases: Apicomplexan Parasites; Becker, K., Ed.; Wiley-VCH: Weinheim, Germany, 2011; Vol. 2, pp 319-334.
13. Lemercier, G.; Fernandez-Montalvan, A.; Shaw, J. P.; Kugelstadt, D.; Bomke, J.; Domostoj, M.; Schwarz, M. K.; Scheer, A.; Kappes, B.; Leroy, D. Identification and characterization of novel small molecules as potent inhibitors of the plasmodial calcium-dependent protein kinase 1 Biochemistry 2009, 48, 6379-6389
14. Lourido, S.; Zhang, C.; Lopez, M. S.; Tang, K.; Barks, J.; Wang, Q.; Wildman, S. A.; Shokat, K. M.; Sibley, L. D. Optimizing small molecule inhibitors of calcium-dependent protein kinase 1 to prevent infection by Toxoplasma gondii J. Med. Chem. 2013, 56, 3068-3077
15. Johnson, S. M.; Murphy, R. C.; Geiger, J. A.; DeRocher, A. E.; Zhang, Z.; Ojo, K. K.; Larson, E. T.; Perera, B. G. K.; Dale, E. J.; He, P.; Reid, M. C.; Fox, A. M. W.; Mueller, N. R.; Merritt, E. A.; Fan, E.; Parsons, M.; Van Voorhis, W. C.; Maly, D. J. Development of Toxoplasma gondii calcium-dependent protein kinase 1 (TgCDPK1) inhibitors with potent anti-toxoplasma activity J. Med. Chem. 2012, 55, 2416-2426
16. Zhang, Z.; Ojo, K. K.; Johnson, S. M.; Larson, E. T.; He, P.; Geiger, J. A.; Castellanos-Gonzalez, A.; White, A. C.; Parsons, M.; Merritt, E. A.; Maly, D. J.; Verlinde, C. L. M. J.; Van Voorhis, W. C.; Fan, E. Benzoylbenzimidazole- based selective inhibitors targeting Cryptosporidium parvum and Toxoplasma gondii calcium-dependent protein kinase-1 Bioorg. Med. Chem. Lett. 2012, 22, 5264-5267
17. Chapman, T. M.; Osborne, S. A.; Bouloc, N.; Large, J. M.; Wallace, C.; Birchall, K.; Ansell, K. H.; Jones, H. M.; Taylor, D.; Clough, B.; Green, J. L.; Holder, A. A. Substituted imidazopyridazines are potent and selective inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) Bioorg. Med. Chem. Lett. 2013, 23, 3064-3069
18. Ojo, K. K.; Larson, E. T.; Keyloun, K. R.; Castaneda, L. J.; DeRocher, A. E.; Inampudi, K. K.; Kim, J. E.; Arakaki, T. L.; Murphy, R. C.; Zhang, L.; Napuli, A. J.; Maly, D. J.; Verlinde, C. L.; Buckner, F. S.; Parsons, M.; Hol, W. G.; Merritt, E. A.; Van Voorhis, W. C. Toxoplasma gondii calcium-dependent protein kinase 1 is a target for selective kinase inhibitors Nat. Struct. Mol. Biol. 2010, 17, 602-607
19. Schrödinger Release 2010, Schrödinger LLC: New York, NY, 2010.
20. Niesen, F. H.; Berglund, H.; Vedadi, M. The use of differential scanning fluorimetry to detect ligand interactions that promote protein stability Nat. Protoc. 2007, 2, 2212-2221
21. Peters, W.; Robinson, B. L. Malaria. In Handbook of Animal Models of Infection; Zak, O.; Sande, M. A., Eds.; Academic Press: San Diego, CA, 1999; pp 757-773.
22. ACD/PhysChem Suite 7, version 12.01; Advanced Chemistry Development, Inc.: Toronto, ON, Canada. www.acdlabs.com.
23. Large, J. M.; Osborne, S. A.; Smiljanic-Hurley, E.; Ansell, K. H.; Jones, H. M.; Taylor, D. L.; Clough, B.; Green, J. L.; Holder, A. A. Imidazopyridazines as potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1): Preparation and evaluation of pyrazole linked analogues Bioorg. Med. Chem. Lett. 2013, 23, 6019-6024
24. Angulo-Barturen, I.; Jiménez-Díaz, M. B.; Mulet, T.; Rullas, J.; Herreros, E.; Ferrer, S.; Jiménez, E.; Mendoza, A.; Regadera, J.; Rosenthal, P. J.; Bathurst, I.; Pompliano, D. L.; Gómez de las Heras, F.; Gargallo-Viola, D. A murine model of falciparum-malaria by in vivo selection of competent strains in non-myelodepleted mice engrafted with human erythrocytes PLoS One 2008, 3, e2252
25. Jebiwott, S.; Govindaswamy, K.; Mbugua, A.; Bhanot, P. Plasmodium berghei calcium dependent protein kinase 1 is not required for host cell invasion PLoS One 2013, 8, e79171
26. Franke-Fayard, B.; Trueman, H.; Ramesar, J.; Mendoza, J.; van der Keur, M.; van der Linden, R.; Sinden, R. E.; Waters, A. P.; Janse, C. J. A Plasmodium berghei reference line that constitutively expresses GFP at a high level throughout the complete life cycle Mol. Biochem. Parasitol. 2004, 137, 23-33