Identification of 6-amino-1H-pyrazolo[3,4-d]pyrimidines with in vivo efficacy against visceral leishmaniasis.

Michael G Thomas,Juan Miguel-Siles,Sujatha Manthri,Paul G Wyatt,Alain Daugan,Laste Stojanovski,Kevin D Read,Gloria Fra,Ian H Gilbert,Franck Martin,Jennifer Riley,Frederick R C Simeons,Manu De Rycker,Lorna Maclean,Timothy J Miles,Claire J Mackenzie,Myriam Ajakane,Yoko Shishikura,César Guerrero,Suzanne Norval,John Thomas,Stephen Thompson,Sabrinia Crouch ,Raúl F Velasco ,Louise Campbell ,José M Fiandor ,Maria Osuna‐Cabello

doi:10.1039/d0md00203h

Abstract

Visceral leishmaniasis (VL) affects millions of people across the world, largely in developing nations. It is fatal if left untreated and the current treatments are inadequate. As such, there is an urgent need for new, improved medicines. In this paper, we describe the identification of a 6-amino-N-(piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine scaffold and its optimization to give compounds which showed efficacy when orally dosed in a mouse model of VL.

Highlights

Visceral leishmaniasis (VL) is caused by infection with the protozoan parasites L. donovani and L. infantum and is typically fatal unless treated, infecting around 50 000–90 000 people annually and resulting in a death toll of between 20 000–30 000.1,2 Current therapies suffer from numerous issues such as high cost, problematic modes of dosing, and toxicity.3 In addition, the global development pipeline for VL is sparse with four additional new chemical entities (NCEs) just entering the early pre-clinical phase.4–7 There is an urgent need for new therapeutic classes to help tackle this neglected disease
Due to a lack of validated druggable targets for VL, we focused on chemical series that showed antiparasitic activity in an assay a Drug Discovery Unit, Wellcome Centre for Anti-Infectives Research, Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee, Dundee DD1 5EH, UK
For the identification of DDD853651/GSK3186899, which contained a trans-1,4-cyclohexyldiamine, a key strategy was to optimise the balance between potency in the intracellular Leishmania assay (L. donovani in THP-1 cells, referred to as Ld InMac assay9) and solubility

Summary

Introduction

Visceral leishmaniasis (VL) is caused by infection with the protozoan parasites L. donovani and L. infantum and is typically fatal unless treated, infecting around 50 000–90 000 people annually and resulting in a death toll of between 20 000–30 000.1,2 Current therapies suffer from numerous issues such as high cost, problematic modes of dosing, and toxicity.3 In addition, the global development pipeline for VL is sparse with four additional new chemical entities (NCEs) just entering the early pre-clinical phase.4–7 There is an urgent need for new therapeutic classes to help tackle this neglected disease. As previously discussed,10 in order to progress to in vivo studies we targeted compounds with pEC50 > 5.8, solubility > 100 μM and intrinsic clearance (Cli) < 5.0 ml min−1 g−1 (mouse liver microsomes), so we explored the SAR around 4, initially focusing on the amide substituent.

Results

Conclusion