Topical Treatment for Cutaneous Leishmaniasis: Dermato-Pharmacokinetic Lead Optimization of Benzoxaboroles.

Cutaneous leishmaniasis (CL) is caused by several species of the protozoan parasite Leishmania, affecting an estimated 10 million people worldwide. Previously reported strategies for the development of topical CL treatments have focused primarily on drug permeation and formulation optimization as the means to increase treatment efficacy. Our approach aims to identify compounds with antileishmanial activity and properties consistent with topical administration. Of the test compounds, five benzoxaboroles showed potent activity (50% effective concentration [EC50] < 5 μM) against intracellular amastigotes of at least one Leishmania species and acceptable activity (20 μM < EC50 < 30 μM) against two more species. Benzoxaborole compounds were further prioritized on the basis of the in vitro evaluation of progression criteria related to skin permeation, such as the partition coefficient and solubility. An MDCKII-hMDR1 cell assay showed overall good permeability and no significant interaction with the P-glycoprotein transporter for all substrates except LSH002 and LSH031. The benzoxaboroles were degraded, to some extent, by skin enzymes but had stability superior to that of para-hydroxybenzoate compounds, which are known skin esterase substrates. Evaluation of permeation through reconstructed human epidermis showed LSH002 to be the most permeant, followed by LSH003 and LSH001. Skin disposition studies following finite drug formulation application to mouse skin demonstrated the highest permeation for LSH001, followed by LSH003 and LSH002, with a significantly larger amount of LSH001 than the other compounds being retained in skin. Finally, the efficacy of the leads (LSH001, LSH002, and LSH003) against Leishmania major was tested in vivo LSH001 suppressed lesion growth upon topical application, and LSH003 reduced the lesion size following oral administration

SCYX-7158, an Orally-Active Benzoxaborole for the Treatment of Stage 2 Human African Trypanosomiasis

Human African trypanosomiasis (HAT) is caused by infection with the parasite Trypanosoma brucei and is an important public health problem in sub-Saharan Africa. New, safe, and effective drugs are urgently needed to treat HAT, particularly stage 2 disease where the parasite infects the brain. Existing therapies for HAT have poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. Through an integrated drug discovery project, we have discovered and optimized a novel class of boron-containing small molecules, benzoxaboroles, to deliver SCYX-7158, an orally active preclinical drug candidate. SCYX-7158 cured mice infected with T. brucei, both in the blood and in the brain. Extensive pharmacokinetic characterization of SCYX-7158 in rodents and non-human primates supports the potential of this drug candidate for progression to IND-enabling studies in advance of clinical trials for stage 2 HAT

Species-Selective Pyrimidineamine Inhibitors of <i>Trypanosoma brucei S</i>-Adenosylmethionine Decarboxylase

New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite <i>Trypanosoma brucei</i>. <i>S</i>-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of <i>T. brucei</i>. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a <i>T. brucei</i> AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for <i>T. brucei</i> AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood–brain barrier penetration. The medicinal chemistry program elucidated structure–activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of <i>Tb</i>AdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization

Species-Selective Pyrimidineamine Inhibitors of <i>Trypanosoma brucei S</i>-Adenosylmethionine Decarboxylase

New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite <i>Trypanosoma brucei</i>. <i>S</i>-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of <i>T. brucei</i>. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a <i>T. brucei</i> AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for <i>T. brucei</i> AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood–brain barrier penetration. The medicinal chemistry program elucidated structure–activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of <i>Tb</i>AdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization

Species-Selective Pyrimidineamine Inhibitors of <i>Trypanosoma brucei S</i>-Adenosylmethionine Decarboxylase

New therapeutic options are needed for treatment of human African trypanosomiasis (HAT) caused by protozoan parasite <i>Trypanosoma brucei</i>. <i>S</i>-Adenosylmethionine decarboxylase (AdoMetDC) is an essential enzyme in the polyamine pathway of <i>T. brucei</i>. Previous attempts to target this enzyme were thwarted by the lack of brain penetration of the most advanced series. Herein, we describe a <i>T. brucei</i> AdoMetDC inhibitor series based on a pyrimidineamine pharmacophore that we identified by target-based high-throughput screening. The pyrimidineamines showed selectivity for <i>T. brucei</i> AdoMetDC over the human enzyme, inhibited parasite growth in whole-cell assay, and had good predicted blood–brain barrier penetration. The medicinal chemistry program elucidated structure–activity relationships within the series. Features of the series that were required for binding were revealed by determining the X-ray crystal structure of <i>Tb</i>AdoMetDC bound to one analog. The pyrimidineamine series provides a novel starting point for an anti-HAT lead optimization

SAR of 2-amino and 2,4-diamino pyrimidines with in vivo efficacy against Trypanosoma brucei

A series of 2,4-diaminopyrimidines was investigated and compounds were found to have in vivo efficacy against Trypanosoma brucei in an acute mouse model. However, in vitro permeability data suggested the 2,4-diaminopyrimidenes would have poor permeability through the blood brain barrier. Consequently a series of 4-desamino analogs were synthesized and found to have improved in vitro permeability