期刊
ACS MEDICINAL CHEMISTRY LETTERS
卷 12, 期 9, 页码 1421-1426出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsmedchemlett.1c00216
关键词
Wolbachia; Pyrazolopyrimidine; Onchocerciasis; Filariasis
资金
- Bill & Melinda Gates Foundation
- GHIT grant
Anti-Wolbachia therapy using pyrazolopyrimidine compounds shows promising results in combating filarial diseases by improving metabolic stability and solubility. Phenotypic screening reveals analogues with potent activity against Wolbachia, with lead compound 15f demonstrating strong potential for in vivo studies. Further optimization and development of this compound series for filariasis treatment is highly anticipated.
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.
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