Anti-<i>Wolbachia</i> therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-<i>Wolbachia</i> activity. This paper focuses on the exploration of the SAR for this chemotype, with improvement of metabolic stability and solubility profiles using medicinal chemistry approaches. Organic synthesis has enabled functionalization of the pyrazolopyrimidine core at multiple positions, generating a library of compounds of which many analogues possess nanomolar activity against <i>Wolbachia in vitro</i> with improved DMPK parameters. A lead compound, <b>15f</b>, was selected for <i>in vivo</i> pharmacokinetics (PK) profiling in mice. The combination of potent anti-<i>Wolbachia</i> activity in two <i>in vitro</i> assessments plus the exceptional oral PK profiles in mice puts this lead compound in a strong position for <i>in vivo</i> proof-of-concept pharmacodynamics studies and demonstrates the strong potential for further optimization and development of this series for treatment of filariasis in the future.