ABSTRACT
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.
Subject(s)
Pyrimidines/chemical synthesis , Pyrimidines/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma brucei brucei/drug effects , Amines/chemistry , Animals , Blood-Brain Barrier , Inhibitory Concentration 50 , Mice , Molecular Structure , Permeability , Pyrimidines/chemistry , Quantitative Structure-Activity Relationship , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistryABSTRACT
Human African trypanosomiasis, caused by the kinetoplastid parasite Trypanosoma brucei, affects thousands of people across sub-Saharan Africa, and is fatal if left untreated. Treatment options for this disease, particularly stage 2 disease, which occurs after parasites have infected brain tissue, are limited due to inadequate efficacy, toxicity and the complexity of treatment regimens. We have discovered and optimized a series of benzoxaborole-6-carboxamides to provide trypanocidal compounds that are orally active in murine models of human African trypanosomiasis. A key feature of this series is the presence of a boron atom in the heterocyclic core structure, which is essential to the observed trypanocidal activity. We also report the in vivo pharmacokinetic properties of lead compounds from the series and selection of SCYX-7158 as a preclinical candidate.
Subject(s)
Antiprotozoal Agents/chemistry , Benzoxazoles/chemistry , Trypanosomiasis, African/drug therapy , Administration, Oral , Animals , Antiprotozoal Agents/pharmacokinetics , Antiprotozoal Agents/therapeutic use , Benzamides/chemistry , Benzamides/pharmacokinetics , Benzamides/therapeutic use , Benzoxazoles/pharmacokinetics , Benzoxazoles/therapeutic use , Boron Compounds/chemistry , Boron Compounds/pharmacokinetics , Boron Compounds/therapeutic use , Brain/metabolism , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Male , Mice , Structure-Activity Relationship , Trypanosoma brucei brucei/isolation & purificationABSTRACT
BACKGROUND: Human African trypanosomiasis (HAT) is an important public health problem in sub-Saharan Africa, affecting hundreds of thousands of individuals. An urgent need exists for the discovery and development of new, safe, and effective drugs to treat HAT, as existing therapies suffer from poor safety profiles, difficult treatment regimens, limited effectiveness, and a high cost of goods. We have discovered and optimized a novel class of small-molecule boron-containing compounds, benzoxaboroles, to identify SCYX-7158 as an effective, safe and orally active treatment for HAT. METHODOLOGY/PRINCIPAL FINDINGS: A drug discovery project employing integrated biological screening, medicinal chemistry and pharmacokinetic characterization identified SCYX-7158 as an optimized analog, as it is active in vitro against relevant strains of Trypanosoma brucei, including T. b. rhodesiense and T. b. gambiense, is efficacious in both stage 1 and stage 2 murine HAT models and has physicochemical and in vitro absorption, distribution, metabolism, elimination and toxicology (ADMET) properties consistent with the compound being orally available, metabolically stable and CNS permeable. In a murine stage 2 study, SCYX-7158 is effective orally at doses as low as 12.5 mg/kg (QD×7 days). In vivo pharmacokinetic characterization of SCYX-7158 demonstrates that the compound is highly bioavailable in rodents and non-human primates, has low intravenous plasma clearance and has a 24-h elimination half-life and a volume of distribution that indicate good tissue distribution. Most importantly, in rodents brain exposure of SCYX-7158 is high, with C(max) >10 µg/mL and AUC(0-24 hr) >100 µg*h/mL following a 25 mg/kg oral dose. Furthermore, SCYX-7158 readily distributes into cerebrospinal fluid to achieve therapeutically relevant concentrations in this compartment. CONCLUSIONS/SIGNIFICANCE: The biological and pharmacokinetic properties of SCYX-7158 suggest that this compound will be efficacious and safe to treat stage 2 HAT. SCYX-7158 has been selected to enter preclinical studies, with expected progression to phase 1 clinical trials in 2011.
Subject(s)
Antiprotozoal Agents/administration & dosage , Antiprotozoal Agents/pharmacokinetics , Benzamides/administration & dosage , Benzamides/pharmacokinetics , Boron Compounds/administration & dosage , Boron Compounds/pharmacokinetics , Trypanosomiasis, African/drug therapy , Administration, Oral , Animals , Antiprotozoal Agents/adverse effects , Benzamides/adverse effects , Boron Compounds/adverse effects , Disease Models, Animal , Female , Mice , Parasitic Sensitivity Tests , Primate Diseases/drug therapy , Primates , Rodent Diseases/drug therapy , Treatment Outcome , Trypanosoma/drug effectsABSTRACT
Mifepristone is a non-selective antagonist of 3-oxosteroid receptors with both abortifacient and anti-endometriotic activities. Non-steroidal mimetics of mifepristone and progesterone are important templates for modulation of the progesterone receptor (PR). For our PR program, we sought an unexplored, synthetically accessible non-steroidal mimetic of mifepristone, suitable for parallel synthesis of analogues. Docking of compounds into a PR homology model identified 4-substituted pyrazolines, which, when synthesized and tested, exhibited functional antagonism of PR.