Discovery of Q203, a potent clinical candidate for the treatment of tuberculosis

1] Institut Pasteur Korea, Sampyeong-dong, Seongnam-si, Gyeonggi-do, Korea. [2].
Nature medicine (Impact Factor: 27.36). 08/2013; 19(9). DOI: 10.1038/nm.3262
Source: PubMed


New therapeutic strategies are needed to combat the tuberculosis pandemic and the spread of multidrug-resistant (MDR) and extensively drug-resistant (XDR) forms of the disease, which remain a serious public health challenge worldwide. The most urgent clinical need is to discover potent agents capable of reducing the duration of MDR and XDR tuberculosis therapy with a success rate comparable to that of current therapies for drug-susceptible tuberculosis. The last decade has seen the discovery of new agent classes for the management of tuberculosis, several of which are currently in clinical trials. However, given the high attrition rate of drug candidates during clinical development and the emergence of drug resistance, the discovery of additional clinical candidates is clearly needed. Here, we report on a promising class of imidazopyridine amide (IPA) compounds that block Mycobacterium tuberculosis growth by targeting the respiratory cytochrome bc1 complex. The optimized IPA compound Q203 inhibited the growth of MDR and XDR M. tuberculosis clinical isolates in culture broth medium in the low nanomolar range and was efficacious in a mouse model of tuberculosis at a dose less than 1 mg per kg body weight, which highlights the potency of this compound. In addition, Q203 displays pharmacokinetic and safety profiles compatible with once-daily dosing. Together, our data indicate that Q203 is a promising new clinical candidate for the treatment of tuberculosis.

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Available from: Sung-Jun Han, Jul 16, 2014
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    • "The discovery of bedaquiline highlighted energy metabolism in general and ATP synthase inhibition in particular as highly druggable. Very recently, Pethe and colleagues further validated the protonmotive force and ATP synthesis as a major TB drug target with the discovery of a new class of imidazopyridine amide compounds that block growth of Mtb by targeting the respiratory cytochrome bc 1 complex (Pethe et al, 2013). Using phenotypic high-content screening of infected macrophages (described in detail later), a series of compounds were selected and chemically optimized culminating in Q203, an inhibitor active at nanomolar concentrations with promising efficacy in murine TB models. "
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    • "This was determined through genomic sequencing of spontaneous BCG resistant mutants and identification of a common target, qcrB, as well as the over-expression of QcrB in BCG resulting in a >10 fold increase in MIC to different imidazo[1,2-a]pyridines compounds. Pethe et al. also found their IPA Q203 targets the qcrB [10]. At present it is unclear whether there are additional targets for imidazo[1,2-a]pyridines but the ability of this family of compounds to target a major component of the electron transport chain shows great promise as a mechanism of action. "
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