867267-25-2Relevant academic research and scientific papers
Synthetic studies to help elucidate the metabolism of the preclinical candidate TBAJ-876—a less toxic and more potent analogue of bedaquiline
Choi, Peter J.,Conole, Daniel,Sutherland, Hamish S.,Blaser, Adrian,Tong, Amy S.T.,Cooper, Christopher B.,Upton, Anna M.,Palmer, Brian D.,Denny, William A.
, (2020/03/26)
Bedaquiline is a novel drug approved in 2012 by the FDA for treatment of drug-resistant tuberculosis (TB). Although it shows high efficacy towards drug-resistant forms of TB, its use has been limited by the potential for significant side effects. In particular, bedaquiline is a very lipophilic compound with an associated long terminal half-life and shows potent inhibition of the cardiac potassium hERG channel, resulting in QTc interval prolongation in humans that may result in cardiac arrhythmia. To address these issues, we carried out a drug discovery programme to develop an improved second generation analogue of bedaquiline. From this medicinal chemistry program, a candidate (TBAJ-876) has been selected to undergo further preclinical evaluation. During this evaluation, three major metabolites arising from TBAJ-876 were observed in several preclinical animal models. We report here our synthetic efforts to unequivocally structurally characterize these three metabolites through their independent directed synthesis.
3,5-Dialkoxypyridine analogues of bedaquiline are potent antituberculosis agents with minimal inhibition of the hERG channel
Sutherland, Hamish S.,Tong, Amy S.T.,Choi, Peter J.,Blaser, Adrian,Conole, Daniel,Franzblau, Scott G.,Lotlikar, Manisha U.,Cooper, Christopher B.,Upton, Anna M.,Denny, William A.,Palmer, Brian D.
, p. 1292 - 1307 (2019/02/25)
Bedaquiline is a new drug of the diarylquinoline class that has proven to be clinically effective against drug-resistant tuberculosis, but has a cardiac liability (prolongation of the QT interval) due to its potent inhibition of the cardiac potassium channel protein hERG. Bedaquiline is highly lipophilic and has an extremely long terminal half-life, so has the potential for more-than-desired accumulation in tissues during the relatively long treatment durations required to cure TB. The present work is part of a program that seeks to identify a diarylquinoline that is as potent as bedaquiline against Mycobacterium tuberculosis, with lower lipophilicity, higher clearance, and lower risk for QT prolongation. Previous work led to the identification of compounds with greatly-reduced lipophilicity compounds that retain good anti-tubercular activity in vitro and in mouse models of TB, but has not addressed the hERG blockade. We now present compounds where the C-unit naphthalene is replaced by a 3,5-dialkoxy-4-pyridyl, demonstrate more potent in vitro and in vivo anti-tubercular activity, with greatly attenuated hERG blockade. Two examples of this series are in preclinical development.
Solvent-dependent oxidations of 5- and 6-azaindoles to trioxopyrrolopyridines and functionalised azaindoles
Mahiout, Zahia,Lomberget, Thierry,Goncalves, Sylvie,Barret, Roland
supporting information; experimental part, p. 1364 - 1376 (2008/10/09)
A regioselective synthesis of 4,7-dimethoxy 5- and 6-azaindoles 2 has been achieved, based on the appropriate choice of ortho-directing or ortho-repulsing groups in the formylation of a pyridine ring. Studies on the regioselectivity of the formylation step and on the preparation of azidoacrylate intermediates 4 are described in this paper. The reactivity of the 5- and 6-azaindole structures towards BBr3-mediated selective monodemethylation and oxidative demethylation reactions were also investigated. The regioselectivity of the deprotection was confirmed using a chemical approach. Oxidation reactions were then carried out on either dimethoxy- or hydroxymethoxyazaindoles, in different solvents, using [bis(trifluoroacetoxy)iodo]benzene. In acetonitrile-water, trioxopyrrolopyridines 12 were obtained, whereas the formation of functionalised azaindoles 17 was observed in acetonitrile-methanol. The tautomeric structure of the trioxopyrrolopyridines was proved by X-ray diffraction analysis. The Royal Society of Chemistry.
A regioselective route to 5- and 6-azaindoles
Lomberget, Thierry,Radix, Sylvie,Barret, Roland
, p. 2080 - 2082 (2007/10/03)
The synthesis of 4,7-dimethoxy 5- and 6-azaindoles, a structural unit that is present in recently developed anti-HIV-1 agents, was achieved in a regioselective manner. The developed strategy is based on the appropriate choice of a protecting group during a lithium-mediated formylation step, followed by thermal cyclization of azidoacrylates. Georg Thieme Verlag Stuttgart.
