Design, Syntheses and Studies of Novel Antituberculosis Agents

点击翻译按钮获取中文摘要

Tuberculosis (TB) is a highly contagious airborne pathogen that infects > 2 billion people, of whom an estimated 1.5 million people per year are killed by the disease. The global spread of multi-drug resistant (MDR), extensively- drug resistant (XDR), and totally drug resistant (TDR) strains of tuberculosis emphasizes the great need for new effective treatments. This renewal resubmission application capitalizes on the discovery of two hit series – the imidazo[1,2-a]pyridine-3-carboxamides and the imidazo[2,1-b]thiazole-5-carboxamides – and seeks to advance these to potential TB treatments. As the first to patent, prolifically publish, and propose the mechanism of action for the imidazo[1,2-a]pyridine-3-carboxamide (IAPC) series, we are the most experienced group to continue development of this series through primate evaluation in preparation for clinical (human) studies. Recently, we had the PK of two lead compounds evaluated in primates with one ND-10885 showing great exposure (>20 hours of drug levels above the MIC). Additionally, we have disclosed the impressive in vitro properties of the imidazo[2,1-b]thiazole 5-carboxamide (IT) series, a new promising, rationally designed, scaffold we will develop within this proposal. This new class has low nanomolar antiTB activity against H37Rv, multidrug resistant (MDR) and extreme drug resistant (XDR) Mtb as well as good in vitro metabolism and in vivo exposure with greater lung to plasma ratios. Furthermore, both these heterocyclic scaffolds (IAPC and IT) can be prepared in bulk (50 – 100 g) inexpensively and, from these penultimate intermediates, lead compounds with animal efficacy can be prepared in just one synthetic step (amide bond formation) and in multi- gram quantities (>15 g). Through our extensive collaborations, we will evaluate all samples for antiTB activity [including MDR and XDR strains of Mtb]. We will also perform related studies, including microbe selectivity, gross toxicity particularly looking to avoid mitochondrial toxicity, metabolism, pharmacokinetics (PK), maximum tolerated dose (MTD), mice and/or monkey efficacy and mode of action studies of any new compounds with promising activity and physicochemical attributes including metabolite identification. Our criteria for a clinical candidate are: selective nanomolar potency against H37Rv and drug resistant Mtb, in vivo efficacy comparable to first line drugs isoniazid and rifampicin (at a dose <100 mg/kg), low toxicity (at least 10x over effective dose), minimal drug-drug interactions, good aqueous solubility (>100 µg/mL) and synthetic simplicity/cost effectiveness. A highly qualified team of coworkers and collaborators from experienced laboratories from academia, industry and the NIH has been assembled to accomplish the overarching goal of providing the TB- research and biomedical communities the second new drug treatment in 40 years as well as a validated new drug target (respiratory bc1 complex of Mtb).