175 synthesis br Chagas disease and HAT drug
Chagas disease and HAT drug R&D Drug R&D for Chagas disease and HAT has historically relied on serendipitous findings achieved using low-technology approaches. The absence of biotechnology tools associated and the very limited understanding of the biomolecular processes of the parasites are among the major 175 synthesis that have delayed the development of technology-based drug discovery platforms. Significant improvement has been made in the past 10years, prompted by the publication of the genome of T. cruzi and T. brucei (Berriman et al., 2005, El-Sayed et al., 2005). These discoveries have established the basis for the understanding of key aspects of the parasite-host interaction, which have been successfully translated into structured drug discovery programs. Simultaneously, the engagement of PPPs in the R&D process has provided appropriate infrastructure and technology to the field, which has enabled the use of experimental models that were previously seldom accessible, consequently contributing to the establishment of robust preclinical and clinical profiling programs (Cohen, Sturgeon, & Cohen, 2014). For example, high-throughput screening campaigns for the evaluation of compound libraries in the pharmaceutical industry is a common procedure (Goupil & McKerrow, 2014). Other key advances include improved reproducibility of the assays and validation of the experimental procedures. Undoubtedly, these scientific, technological and organizational gains have positively affected current Chagas disease and HAT drug R&D. Altogether, these advances have culminated in solid R&D programs that integrate complementary methodologies in drug discovery, such as target-based and phenotypic screenings (Don & Ioset, 2014). Compounds identified by these approaches undergo molecular optimization studies, in which diverse medicinal chemistry strategies are employed. This can be exemplified by a few compounds that have recently reached clinical trials for Chagas disease and HAT. Oxaboroles, for instance, have demonstrated promising results in HAT preclinical and clinical development. SCYX-7158 (7, Fig. 3), an oxaborole developed in a PPP led by the Drugs for Neglected Diseases Initiative (DNDi), is a promising candidate for oral treatment of late-stage HAT. In the preclinical phase, the compound showed suitable physicochemical and in vitro absorption, distribution, metabolism, elimination and toxicity (ADMET) properties, which were consistent with the observed oral bioavailability, metabolic stability and CNS permeability (Jacobs et al., 2011). SCYX-7158 proved effective and safe in murine models of neurological HAT when given orally at doses of 12.5mg/kg (QD×7days). The compound is currently in phase III clinical trials. As part of the same oxaborole project, comprehensive pharmacokinetics profiling of a series of SCYX-7158 analogs led to the selection of SCYX-1608210 (8) and SCYX-1330682 (9). These lead compounds demonstrated the ability to cure the disease in preclinical animal models of late-stage HAT and are considered backup alternatives for SCYX-7158. The mechanism of action of oxaboroles remains unknown. In another PPP, DNDi developed fexinidazole (10, Fig. 3), the most advanced drug candidate under development for HAT (phase III clinical trials). The goal of the project is to obtain a cure with a 10-day oral treatment. In a clinical study with 154 healthy adult males from sub-Saharan Africa, fexinidazole was well tolerated when given in single doses from 100mg to 3600mg. A dosing regimen of 1800mg for 4days and 1200mg for the following 6days was found to achieve the required effective drug concentration with an acceptable safety profile (Tarral et al., 2014). Fexinidazole has also been evaluated for Chagas disease. Preclinical investigations have shown that the compound reduces parasite burden and prevents death among infected mice. High cure rates were obtained (approximately 80% to 90%) by treating animals during the acute phase with a dosing regimen of 300mg/kg of body weight for 20days. In the chronic phase, a cure rate of 70% was registered with a dosage of 300mg/kg for 20days (Bahia et al., 2012). Fexinidazole has advanced to clinical trials and has proved highly effective and well tolerated at low doses and in different treatment durations. Safety issues have been detected at high doses given for >14days.