Calcium dependent protein kinase 1 (CDPK1) is an essential Ser/Thr kinase that controls invasion and egress by the protozoan parasite <i>Toxoplasma gondii</i>. The Gly gatekeeper of CDPK1 makes it exquisitely sensitive to inhibition by small molecule 1<i>H</i>-pyrazolo[3,4-<i>d</i>]pyrimidine-4-amine (PP) compounds that are bulky ATP mimetics. Here we rationally designed, synthesized, and tested a series of novel PP analogs that were evaluated for inhibition of CDPK1 enzyme activity <i>in vitro</i> and parasite growth in cell culture. Optimal substitution on the PP scaffold included 2-pyridyl ethers directed into the hydrophobic pocket and small carbocyclic rings accessing the ribose-binding pocket. Further optimization of the series led to identification of the lead compound <b>3a</b> that displayed excellent potency, selectivity, safety profile, and efficacy <i>in vivo</i>. The results of these studies provide a foundation for further work to optimize CDPK1 inhibitors for the treatment of acute and chronic toxoplasmosis.