SAR Studies of 5-Aminopyrazole-4-carboxamide Analogues as Potent and Selective Inhibitors of Toxoplasma gondii CDPK1

ACS Med Chem Lett. 2015 Oct 22;6(12):1184-1189. eCollection 2015.

Huang W1, Ojo KK2, Zhang Z1, Rivas K2, Vidadala RS3, Scheele S4, DeRocher AE4, Choi R2, Hulverson MA2, Barrett LK2, Bruzual I5, Siddaramaiah LK1, Kerchner KM1, Kurnick MD6, Freiberg GM6, Kempf D6, Hol WG1, Merritt EA1, Neckermann G7, de Hostos EL7, Isoherranen N8, Maly DJ3, Parsons M9, Doggett JS5, Van Voorhis WC10, Fan E1.

Author information

Abstract

We previously discovered compounds based on a 5-aminopyrazole-4-carboxamide scaffold to be potent and selective inhibitors of CDPK1 from T. gondii. The current work, through structure-activity relationship studies, led to the discovery of compounds (34 and 35) with improved characteristics over the starting inhibitor 1 in terms of solubility, plasma exposure after oral administration in mice, or efficacy on parasite growth inhibition. Compounds 34 and 35 were further demonstrated to be more effective than 1 in a mouse infection model and markedly reduced the amount of T. gondii in the brain, spleen, and peritoneal fluid, and 35 given at 20 mg/kg eliminated T. gondii from the peritoneal fluid.

KEYWORDS: 

Toxoplasma gondii; calcium-dependent protein kinase-1; enzyme inhibitor; structure−activity relationship studies

PMID:

 

26693272

 

[PubMed]