A structural insight of bedaquiline for the cardiotoxicity and hepatotoxicity

Patel, Harun; Pawara, Rahul; Pawara, Kisan; Ahmed, Faizan; Shirkhedkar, Atul A.; Surana, Sanjay J.

doi:10.1016/j.tube.2019.06.005

Cited by 28 publications

(20 citation statements)

References 25 publications

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“…The hERG potency is increased upon the basicity of the dimethylamino group, which is protonated at physiological pH. A critical factor for BDQ optimization is to then get a proper balance of the lipid solubility and basicity of the terminal dimethylamino group [ 99 ]. There is a great interest in manipulating the BDQ scaffold to obtain second-generation DARQ derivatives with attenuate hERG inhibition and reduced lipophilicity [ 100 , 101 , 102 , 103 , 104 , 105 , 106 ].…”

Section: Classification Of Drugs Targeting Energy-metabolism In mentioning

confidence: 99%

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

et al. 2020

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Tuberculosis remains the world’s top infectious killer: it caused a total of 1.5 million deaths and 10 million people fell ill with TB in 2018. Thanks to TB diagnosis and treatment, mortality has been falling in recent years, with an estimated 58 million saved lives between 2000 and 2018. However, the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb strains is a major concern that might reverse this progress. Therefore, the development of new drugs acting upon novel mechanisms of action is a high priority in the global health agenda. With the approval of bedaquiline, which targets mycobacterial energy production, and delamanid, which targets cell wall synthesis and energy production, the energy-metabolism in Mtb has received much attention in the last decade as a potential target to investigate and develop new antimycobacterial drugs. In this review, we describe potent anti-mycobacterial agents targeting the energy-metabolism at different steps with a special focus on structure-activity relationship (SAR) studies of the most advanced compound classes.

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Section: Classification Of Drugs Targeting Energy-metabolism In mentioning

confidence: 99%

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

et al. 2020

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“…However, C797S point mutation and/or other mechanisms have been shown to be associated with the acquired resistance to irreversible EGFR TKIs, which make NSCLC refractory to these inhibitors. [14][15][16][17] The fourth-generation EGFR TKIs such as EAI045 18 and other noncovalent inhibitors, [19][20][21] which target allosteric binding site(s), appear to be a major breakthrough against these tertiary mutations. Despite that, there is still an unmet medical need to develop novel small-molecule inhibitors or therapeutic approaches to overcome multipoint mutations of EGFR.…”

Section: Introductionmentioning

confidence: 99%

Discovery of Potent and Selective Epidermal Growth Factor Receptor (EGFR) Bifunctional Small-Molecule Degraders

Cheng¹,

Lu³

et al. 2020

J. Med. Chem.

124

101

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Several epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been developed and approved by Food and Drug Administration for the treatment of non-small-cell lung cancers, but their efficacy can be compromised by acquired drug resistance conferred by EGFR-mutant variants. Here, we described the discovery of a novel E3 ligase von Hippel-Lindau-recruiting EGFR degrader, MS39 (compound 6), and a first-in-class E3 ligase cereblon-recruiting EGFR degrader, MS154 (compound 10), using the proteolysis targeting chimera technology. These compounds potently induced the degradation of mutant but not wild-type EGFR in an E3 ligasedependent manner in cancer cell lines and effectively suppressed the growth of lung cancer cells

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“…39 Owing to its long half-life and highly lipophilic nature, bedaquiline is known to prolong the QT interval (mainly driven by metabolite M2); additionally, hepatotoxicity is one of its known adverse drug reactions. 40,41 In the present study, no deaths, serious AEs, or TEAEs leading to discontinuation were reported. No laboratory or ECG abnormality was reported as a TEAE; however, the sample size was small and safety still needs to be assessed in the target population.…”

Section: Discussionmentioning

confidence: 45%

“…Owing to its long half‐life and highly lipophilic nature, bedaquiline is known to prolong the QT interval (mainly driven by metabolite M2); additionally, hepatotoxicity is one of its known adverse drug reactions 40,41 . In the present study, no deaths, serious AEs, or TEAEs leading to discontinuation were reported.…”

Section: Discussionmentioning

confidence: 50%

Population Pharmacokinetic Analysis of Bedaquiline‐Clarithromycin for Dose Selection Against Pulmonary Nontuberculous Mycobacteria Based on a Phase 1, Randomized, Pharmacokinetic Study

Kurosawa¹,

Rossenu

Biewenga

et al. 2021

The Journal of Clinical Pharma

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Based on the in vitro profile of bedaquiline against mycobacterial species, it is being investigated for clinical efficacy against pulmonary nontuberculous mycobacteria (PNTM). Being a cytochrome P450 3A substrate, pharmacokinetic interactions of bedaquiline are anticipated with clarithromycin (a cytochrome P450 3A inhibitor), which is routinely used in pulmonary nontuberculous mycobacteria treatment. This phase 1, randomized, crossover study assessed the impact of steady-state clarithromycin (500 mg every 12 hours for 14 days) on the pharmacokinetics of bedaquiline and its metabolite (M2) after single-dose bedaquiline (100 mg; n = 16). Using these data, population pharmacokinetic modeling and simulation analyses were performed to determine the effect of clarithromycin on steady-state bedaquiline exposure. Although no effect was observed on maximum plasma concentration of bedaquiline and time to achieve maximum plasma concentration, its mean plasma exposure increased by 14% after 10 days of clarithromycin coadministration, with slower formation of M2. Simulations showed that bedaquiline plasma trough concentration at steady state was higher (up to 41% until week 48) with clarithromycin coadministration as compared to its monotherapy (400 mg once daily for 2 weeks, followed by 200 mg 3 times a week for 46 weeks; reference regimen). The overall exposure of a simulated bedaquiline regimen (400 mg once dialy for 2 weeks, followed by 200 mg twice a week for 46 weeks) with clarithromycin was comparable (<15% difference) to the monotherapy. Overall, combination of bedaquiline (400 mg once daily for 2 weeks, followed by 200 mg twice a week for 46 weeks) with clarithromycin seems a suitable regimen to be explored for efficacy and safety against pulmonary nontuberculous mycobacteria.

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A structural insight of bedaquiline for the cardiotoxicity and hepatotoxicity

Cited by 28 publications

References 25 publications

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

SAR Analysis of Small Molecules Interfering with Energy-Metabolism in Mycobacterium tuberculosis

Discovery of Potent and Selective Epidermal Growth Factor Receptor (EGFR) Bifunctional Small-Molecule Degraders

Population Pharmacokinetic Analysis of Bedaquiline‐Clarithromycin for Dose Selection Against Pulmonary Nontuberculous Mycobacteria Based on a Phase 1, Randomized, Pharmacokinetic Study

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