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.
ABSTRACT
Acylaminobenzothiazole hits were identified as potential inhibitors of Trypanosoma cruzi replication, a parasite responsible for Chagas disease. We selected compound 1 for lead optimization, aiming to improve in parallel its anti-T. cruzi activity (IC50 = 0.63 µM) and its human metabolic stability (human clearance = 9.57 mL/min/g). A total of 39 analogues of 1 were synthesized and tested in vitro. We established a multiparametric structure-activity relationship, allowing optimization of antiparasite activity, physicochemical parameters, and ADME properties. We identified compound 50 as an advanced lead with an improved anti-T. cruzi activity in vitro (IC50 = 0.079 µM) and an enhanced metabolic stability (human clearance = 0.41 mL/min/g) and opportunity for the oral route of administration. After tolerability assessment, 50 demonstrated a promising in vivo efficacy.
Subject(s)
Chagas Disease/drug therapy , Trypanocidal Agents/chemistry , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Administration, Oral , Animals , Benzothiazoles/chemical synthesis , Benzothiazoles/chemistry , Chlorine/chemistry , Dogs , Female , High-Throughput Screening Assays , Humans , Madin Darby Canine Kidney Cells , Male , Mice , Mice, Inbred C57BL , Mice, Inbred Strains , Microsomes, Liver/drug effects , Parasitic Sensitivity Tests , Structure-Activity Relationship , Trypanocidal Agents/administration & dosage , Trypanocidal Agents/pharmacokineticsABSTRACT
During the course of a research program aimed at identifying novel antileishmanial compounds, a multi-gram synthesis of N-(trans-4-((4-methoxy-3-((R)-3-methylmorpholino)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)amino)cyclohexyl)-2-methylpropane-1-sulfonamide (( R )-1) was required. This letter describes optimisation of the reaction conditions and protecting group strategy for a key Buchwald-Hartwig coupling, delivering the required quantities of ( R )-1, as well as further compounds in the series.
ABSTRACT
The leishmaniases are diseases that affect millions of people across the world, in particular visceral leishmaniasis (VL) which is fatal unless treated. Current standard of care for VL suffers from multiple issues and there is a limited pipeline of new candidate drugs. As such, there is a clear unmet medical need to identify new treatments. This paper describes the optimization of a phenotypic hit against Leishmania donovani, the major causative organism of VL. The key challenges were to balance solubility and metabolic stability while maintaining potency. Herein, strategies to address these shortcomings and enhance efficacy are discussed, culminating in the discovery of preclinical development candidate GSK3186899/DDD853651 (1) for VL.
Subject(s)
Leishmaniasis, Visceral/drug therapy , Morpholines/therapeutic use , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Trypanocidal Agents/therapeutic use , Animals , Female , Hep G2 Cells , Humans , Leishmania donovani/drug effects , Male , Mice, Inbred BALB C , Molecular Structure , Morpholines/chemical synthesis , Morpholines/toxicity , Parasitic Sensitivity Tests , Protein Kinase Inhibitors/chemical synthesis , Protein Kinase Inhibitors/therapeutic use , Protein Kinase Inhibitors/toxicity , Pyrazoles/chemical synthesis , Pyrazoles/toxicity , Pyrimidines/chemical synthesis , Pyrimidines/toxicity , Rats, Sprague-Dawley , Structure-Activity Relationship , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/toxicityABSTRACT
Society urgently needs new, effective medicines for the treatment of tuberculosis. To kick-start the required hit-to-lead campaigns, the libraries of pharmaceutical companies have recently been evaluated for starting points. The GlaxoSmithKline (GSK) library yielded many high-quality hits, and the associated data were placed in the public domain to stimulate engagement by the wider community. One such series, the spiro compounds, are described here. The compounds were explored by a combination of traditional in-house research and open source methods. The series benefits from a particularly simple structure and a short associated synthetic chemistry route. Many members of the series displayed striking potency and low toxicity, and highly promising in vivo activity in a mouse model was confirmed with one of the analogues. Ultimately the series was discontinued due to concerns over safety, but the associated data remain public domain, empowering others to resume the series if the perceived deficiencies can be overcome.
