Development of Pyrazolopyrimidine Anti- Wolbachia Agents for the Treatment of Filariasis

Abstract

Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases. Phenotypic screening revealed a series of pyrazolopyrimidine hits with potent anti-Wolbachia 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 Wolbachia in vitro with improved DMPK parameters. A lead compound, 15f, was selected for in vivo pharmacokinetics (PK) profiling in mice. The combination of potent anti-Wolbachia activity in two in vitro assessments plus the exceptional oral PK profiles in mice puts this lead compound in a strong position for in vivo 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.

Figure 1

Structure of the HTS hit 1 and the pyrazolopyrimidine scaffold with the areas for SAR studies highlighted.

Figure 2

Screening cascade for the design, synthesis and testing of anti-Wolbachia compounds.

Scheme 1. Synthetic Route for Analogues in the Pyrazolopyrimidine Template

Scheme 2. Optimized Route for the Synthesis of Analogues with Modified 3-Positions

Note: THP = Tetrahydropyran.

Chart 1. Mean Plasma Concentration of Compound 15f Following Dosing to SCID Mice with SSV

Figure 3

Summary of the SAR of anti-Wolbachia pyrazolopyrimidines.