Novel Amino-pyrazole Ureas with Potent In Vitro and In Vivo Antileishmanial Activity

J Med Chem. 2015 Dec 24;58(24):9615-24. doi: 10.1021/acs.jmedchem.5b01456.

Charles E Mowbray ¹, Stéphanie Braillard ¹, William Speed ¹, Paul A Glossop ², Gavin A Whitlock ², Karl R Gibson ², James E J Mills ², Alan D Brown ³, J Mark F Gardner ⁴, Yafeng Cao ⁵, Wen Hua ⁵, Garreth L Morgans ⁶, Pim-Bart Feijens ⁷, An Matheeussen ⁷, Louis J Maes ⁷

Affiliations

1 Drugs for Neglected Diseases initiative (DNDi) , 15 Chemin Louis-Dunant, 1202 Geneva, Switzerland.
2 Sandexis Medicinal Chemistry Ltd., Innovation House , Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, United Kingdom.
3 Pfizer Worldwide Medicinal Chemistry , The Portway Building, Granta Park, Great Abington, Cambridge CB21 6GS, United Kingdom.
4 AMG Consultants Ltd., Discovery Park House , Discovery Park, Ramsgate Road, Sandwich, Kent CT13 9ND, United Kingdom.
5 WuXi AppTec (Wuhan) Company Ltd. , 666 Gaoxin Road, East Lake High-Tech Development Zone, Wuhan 430075, People's Republic of China.
6 iThemba Pharmaceuticals , Building T5, Pinelands Site, High Street, Modderfontein 1609, Gauteng, South Africa.
7 Laboratory for Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp , S7, Universiteitsplein 1, 2610 Wilrijk, Antwerp, Belgium.

PMID: 26571076 DOI: 10.1021/acs.jmedchem.5b01456

Abstract

Visceral leishmaniasis is a severe parasitic disease that is one of the most neglected tropical diseases. Treatment options are limited, and there is an urgent need for new therapeutic agents. Following an HTS campaign and hit optimization, a novel series of amino-pyrazole ureas has been identified with potent in vitro antileishmanial activity. Furthermore, compound 26 shows high levels of in vivo efficacy (>90%) against Leishmania infantum, thus demonstrating proof of concept for this series.

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