btz-043

BTZ-043 efficiently inhibits Mtb cell wall synthesis by blocking the decaprenyl- phosphoribose-2′-epimerase (DprE1), necessary for the synthesis of D-Arabinofuranose, a component of arabinogalactan and arabinomannan. Due to this mechanism it is highly selective for Mycobacteria species and does not affect the gut flora. BTZ-043 binds covalently to the enzyme and blocks it irreversibly. BTZ-043 is active against all tested Mtb strains including clinical isolated from MDR and XDR patients. The in vitro MIC ranges between ~0.1 - 80 ng/ml for fast growers, and from 1 - 30 ng/ml for members of the M. tuberculosis complex. In vivo BTZ-043 shows superior activity to INH in mouse models, most prominent after 2 months and thereafter. Synergistic effects with Rifampicin were detected in vitro as well as in vivo. In preclinical toxicology (GLP) studies, BTZ-043 showed a low toxicologic potential, it was well tolerated up to 180 mg/kg in rats. BTZ-043 showed no interaction with the CYP450 enzymes or the hERG channel. Genotoxicity and mutagenicity studies were negative. In vitro metabolism studies implicate an acceptable stability in the human organism with only one main metabolite. Protocols for GMP production in industrial scale are available and high purity of the substance can be achieved easily. Currently the final tolerability studies in two animal models are completed and studies in mice are conducted to better describe the pharmacodynamic drivers. — NCATS