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.
Highlights
Anti-Wolbachia therapy has been identified as a viable treatment for combating filarial diseases
F ilarial nematodes are the causative pathogens of the neglected tropical diseases lymphatic filariasis (LF) and onchocerciasis that affect tens of millions people throughout the tropics and contribute to serious public health and socioeconomic problems
The original hit for this chemotype (1) which resulted from a phenotypic high-throughput screen (HTS) of a divergent chemical library donated by the Medicines for Malaria Venture
Summary
While it is possible to use the appropriate nitriles as starting material for the synthesis of target compounds with different groups at the R1-position, a divergent orientated synthesis at this position was desirable for the production of a number of target analogues from a common intermediate. (Scheme 2). It was demonstrated that the removal of the methyl substituent from the R2-position (15k) was tolerated in terms of potency and resulted in some improvement in DMPK properties when compared to compound 3. After being screened for potency and DMPK properties in vitro, a number of selected analogues were tested at 5 μM alongside the gold-standard doxycycline for comparison of anti-Wolbachia activity in the mf assay. This compound demonstrates good tolerability, excellent in vivo PK profiles with high exposure, reasonable half-life and dose-proportional AUC Based on this data 15f has been selected as a lead for an in vivo proof-of-concept pharmacodynamics study and further optimization.
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