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

McGillan, Paul, Berry, Neil G., Nixon, Gemma L., Leung, Suet C., Webborn, Peter J. H., Wenlock, Mark C., Kavanagh, Stefan, Cassidy, Andrew, Clare, Rachel ORCID: https://orcid.org/0000-0002-3945-0530, Cook, Darren, Johnston, Kelly, Ford, Louise, Ward, Steve ORCID: https://orcid.org/0000-0003-2331-3192, Taylor, Mark ORCID: https://orcid.org/0000-0003-3396-9275, Hong, David and O’Neill, Paul M. (2021) 'Development of Pyrazolopyrimidine Anti-Wolbachia Agents for the Treatment of Filariasis'. ACS Medicinal Chemistry Letters, Vol 12, Issue 9, pp. 1421-1426.

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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.

Item Type:	Article
Subjects:	QV Pharmacology > QV 38 Drug action. WC Communicable Diseases > Tropical and Parasitic Diseases > WC 880 Filariasis and related conditions (General)
Faculty: Department:	Biological Sciences > Department of Tropical Disease Biology Biological Sciences > Vector Biology Department
Digital Object Identifer (DOI):	https://doi.org/10.1021/acsmedchemlett.1c00216
Depositing User:	Cathy Waldron
Date Deposited:	24 Aug 2021 07:07
Last Modified:	20 Sep 2021 16:28
URI:	https://archive.lstmed.ac.uk/id/eprint/18737

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