bedaquiline analogue (TBAJ-587) / Global Alliance for TB Drug Development - LARVOL DELTA

Therapeutic Strategies for Tuberculosis: Progress and Lessons Learned. (PubMed, Biomed Environ Sci) - "Promising agents such as second-generation bedaquiline analogs (TBAJ-587, TBAJ-876), sudapyridine (WX-081), delamanid, pretomanid, and TBI-166 (pyrifazimine) have shown efficacy against resistant Mtb strains...Agents such as vitamin D, corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs), statins, metformin, and biological agents like interleukins and granulocyte-macrophage colony-stimulating factor are under exploration...Despite these advancements, significant challenges remain in achieving the World Health Organization's "End TB Strategy" goals, particularly as the COVID-19 pandemic has diverted resources and attention. Ongoing research and global collaboration are crucial to develop novel therapeutic strategies, optimize treatment regimens, and ultimately reduce the global burden of TB."

Journal • Review • Infectious Disease • Novel Coronavirus Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

TBAJ-587, a novel diarylquinoline, is active against Mycobacterium abscessus. (PubMed, Antimicrob Agents Chemother) - "TBAJ-587 is a novel diarylquinoline, which shows higher anti-tuberculosis activity, lower lipophilicity, and weaker inhibition of hERG channels than bedaquiline (BDQ). TBAJ-587 expressed bactericidal activity and was compatible with eight anti-NTM drugs commonly used in clinical practice; no antagonism was discovered. As such, TBAJ-587 represents a potential candidate for the treatment of NTM infections."

Journal • Infectious Disease • Nontuberculous Mycobacterial Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Inhibition of M. tuberculosis and human ATP synthase by BDQ and TBAJ-587. (PubMed, Nature) - "Bedaquiline (BDQ), a first-in-class diarylquinoline anti-tuberculosis drug, and its analogue, TBAJ-587, prevent the growth and proliferation of Mycobacterium tuberculosis by inhibiting ATP synthase1,2. The structure of human ATP synthase in complex with BDQ reveals that the BDQ-binding site is similar to that observed for the leading site in M. tuberculosis ATP synthase, and that the quinolinyl unit also interacts extensively with the human enzyme. This study will improve researchers' understanding of the similarities and differences between human ATP synthase and M. tuberculosis ATP synthase in terms of the mode of BDQ binding, and will allow the rational design of novel diarylquinolines as anti-tuberculosis drugs."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Telacebec's Contribution to Combination Drug Regimens Is Strain-Dependent in a Mouse Model of Tuberculosis (ATS 2024) - "In H37Rv-infected mice, addition of pyrazinamide or clofazimine significantly increased the bactericidal activity of the next-generation diarylquinoline TBAJ-587, while telacebec did not; nor did telacebec increase the activity of either diarylquinoline TBAJ-587 or TBAJ-876 combined with clofazimine. However, in HN878-infected mice, addition of telacebec significantly increased the activity of bedaquiline+clofazimine ± pretomanid. Likewise, adding telacebec to the pretomanid+linezolid combination was antagonistic in H37Rv-infected mice but additive in HN878-infected mice; and addition of telacebec significantly increased the activity of rifapentine+moxifloxacin+pyrazinamide in HN878-infected, but not H37Rv-infected, mice...These experiments clearly highlight differences in the vulnerability of two commonly used M. tuberculosis strains to telacebec, which impact on its contribution to combination therapy. Recent work suggests that the H37Rv laboratory strain more..."

Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

A novel diarylquinoline, TBAJ-587, is active against Mycobacterium abscessus in vitro (ECCMID 2024) - No abstract available

Preclinical

Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis. (PubMed, Antimicrob Agents Chemother) - "In addition, we found that GSK2556286 and TBA-7371 were as effective as pretomanid and the novel oxazolidinone TBI-223 when either drug pair was combined with TBAJ-587 and that the addition of GSK2556286 increased the bactericidal activity of the TBAJ-587, pretomanid, and TBI-223 combination. We conclude that GSK2556286 and TBA-7371 have the potential to replace pretomanid, an oxazolidinone, or both components, in combination with bedaquiline or TBAJ-587."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Evaluation of the Safety, Tolerability, PK of TBAJ-587 in Healthy Adults (clinicaltrials.gov) - P1 | N=106 | Completed | Sponsor: Global Alliance for TB Drug Development | Active, not recruiting ➔ Completed

Trial completion • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Synergistic Li/Li Bimetallic System for the Asymmetric Synthesis of Antituberculosis Drug TBAJ-587. (PubMed, J Org Chem) - "TBAJ-587, an analogue of the antituberculosis drug bedaquiline (BDQ), bearing a diarylquinoline skeleton retains the high bacterial potency, is less toxic, and has a better pharmacokinetic profile than the parent molecule, which has entered phase I clinical trials. Furthermore, the reaction could be conducted on a 5 g scale, and the product was obtained with 99.9:0.1 er after a simple recrystallization. The realization of this protocol will greatly aid the demand for clinical drug production."

Journal • Infectious Disease • Respiratory Diseases • Tuberculosis

A Novel Tool to Identify Bactericidal Compounds against Vulnerable Targets in Drug-Tolerant M. tuberculosis found in Caseum. (PubMed, mBio) - "By screening drug candidates in the surrogate model, we determined that the bedaquiline analogs TBAJ876 and TBAJ587, currently in clinical development, exhibit superior bactericidal against caseum-resident Mtb, both alone and as substitutions for bedaquiline in the bedaquiline-pretomanid-linezolid regimen approved for the treatment of multidrug-resistant TB. The assay is well suited to screen for bactericidal compounds against caseum-resident Mtb in a medium-throughput format, allowing for reduced reliance on resource intensive animal models that present large necrotic lesions and cavities. Importantly, this approach will aid the identification of vulnerable targets in caseum Mtb and can accelerate the development of novel TB drugs with treatment-shortening potential."

Journal • Infectious Disease • Metabolic Disorders • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Next-Generation Diarylquinolines Improve Sterilizing Activity of Regimens with Pretomanid and the Novel Oxazolidinone TBI-223 in a Mouse Tuberculosis Model. (PubMed, Antimicrob Agents Chemother) - "Replacing linezolid or TBI-223 with sutezolid in combination with TBAJ-587 and pretomanid significantly reduced the proportion of mice relapsing. In combination with pretomanid and TBI-223, TBAJ-876 at 6.25 mg/kg was equipotent to TBAJ-587 at 25 mg/kg. We conclude that replacement of bedaquiline with these more efficacious and potentially safer diarylquinolines and replacement of linezolid with potentially safer and at least as efficacious oxazolidinones in the clinically successful BPaL regimen may lead to superior regimens capable of treating both drug-susceptible and drug-resistant TB more effectively and safely."

Journal • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Evaluation of the Safety, Tolerability, PK of TBAJ-587 in Healthy Adults (clinicaltrials.gov) - P1 | N=106 | Active, not recruiting | Sponsor: Global Alliance for TB Drug Development | Recruiting ➔ Active, not recruiting

Enrollment closed • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Discovery of Anti-tubercular Analogues of Bedaquiline with Modified A-, B- and C-Ring Subunits. (PubMed, ChemMedChem) - "To date, the clinical use of the anti-tubercular therapy bedaquiline has been limited due to safety concerns. Recent investigations determined that modification of the B- and C-ring units of bedaquiline delivered new compounds (for example TBAJ-587) with potent anti-tubercular activity yet an improved safety profile due to reduced affinity for the hERG channel. Building on our recent discovery that substitution of bedaquiline's quinoline motif (the A-ring subunit) for C5-aryl pyridine groups led to retention of anti-tubercular activity, we investigated the concurrent modification of A-, B- and C-ring units within bedaquiline variants. These investigations led to the discovery that 4-trifluoromethoxyphenyl and 4-chlorophenyl pyridyl analogues of TBAJ-587 retained relatively potent anti-tubercular activity and delivered a significant reduction in hERG inhibition relative to bedaquiline, demonstrating that modifications of the A-, B- and C-ring..."

Journal • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

The pipeline of new molecules and regimens against drug-resistant tuberculosis. (PubMed, J Clin Tuberc Other Mycobact Dis) - "The clinical development and regulatory approval of bedaquiline, delamanid and pretomanid over the last decade brought about significant progress in the management of drug-resistant tuberculosis, providing all-oral regimens with favorable safety profiles...Investigational drugs in clinical development that target clinically validated mechanisms, such as second generation oxazolidinones (sutezolid, delpazolid, TBI-223) and diarylquinolines (TBAJ-876 and TBAJ-587) promise improved potency and/or safety compared to the first-in-class drugs. Compounds with novel targets involved in diverse bacterial functions such as cell wall synthesis (DrpE1, MmpL3), electron transport, DNA synthesis (GyrB), cholesterol metabolism and transcriptional regulation of ethionamide bioactivation pathways have advanced to early clinical studies with the potential to enhance antibacterial activity when added to new or established anti-TB drug regimens. Clinical validation of preclinical in vitro..."

Journal • Review • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis • MMP3

Evaluation of the Safety, Tolerability, PK of TBAJ-587 in Healthy Adults (clinicaltrials.gov) - P1; N=100; Recruiting; Sponsor: Global Alliance for TB Drug Development

Clinical • New P1 trial • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis