Figure 1.

Predicted pIs vs experimentally determined IC_50s in the 4-piperidinemethyl R2 series The FLO software was used to predict the pI (inhibition of PfCDPK4 or pI [calc]) vs experimentally determined pIs (pI exp) in the methylpiperidine R² series. There was a correlation of R² = 0.81, thereby validating the model for this series of compounds. The model was used to select variations that retain potency and vary the PK/ADMET properties of the compounds. The successful modeling efforts that predicted potent PfCDPK4 inhibitors demonstrates how we can select potent derivatives of the pyrazolopyrimidine scaffold that are metabolically-stable for PK/ADMET optimization. Abbreviations: pI, –log₁₀ (inhibition constant) PK, pharmacokinetics, ADMET, absorption, distribution, metabolism, excretion, toxicity.