TBA-7371 / Bill & Melinda Gates Foundation, Global Alliance for TB Drug Development, Foundation for Neglected Disease Research - LARVOL DELTA

Discovery of potent DprE1-targeted antitubercular agents: synthesis and evaluation of PBTZ169/TBA7371-based derivatives. (PubMed, Mol Divers) - "Furthermore, molecular dynamics (MD) simulations confirmed the high stability of the 9m -DprE1 complex compared to the standard reference compound. These findings suggest that compound 9m  could lead to the development of novel antitubercular agents."

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

Targeting the Heart of Mycobacterium: Advances in Anti-Tubercular Agents Disrupting Cell Wall Biosynthesis. (PubMed, Pharmaceuticals (Basel)) - "Isoniazid, thioamides, and delamanid primarily disrupt mycolic acid synthesis, with recent evidence indicating that delamanid also inhibits decaprenylphosphoryl-β-D-ribose-2-epimerase, thereby impairing arabinogalactan biosynthesis. Furthermore, ethambutol interferes with arabinogalactan synthesis by targeting arabinosyl transferase enzymes, particularly embB- and embC-encoded variants. Beyond these, six promising molecules currently in Phase II clinical trials are designed to target arabinan synthesis pathways, sutezolid, TBA 7371, OPC-167832, SQ109, and both benzothiazinone derivatives BTZ043 and PBTZ169, highlighting advancements in the development of cell wall-targeting therapies."

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

Targeting decaprenylphosphoryl-β-D-ribose 2'-epimerase for Innovative Drug Development Against Mycobacterium Tuberculosis Drug-Resistant Strains. (PubMed, Bioinform Biol Insights) - "Six compounds, PubChem ID: 390820, 86287492, 155294899, 155522922, 162651615, and 162665075, exhibited promising attributes as drug candidates and validated against clinical trial inhibitors BTZ043, TBA-7371, PBTZ169, and OPC-167832. Integrated computational and pharmacophore methodologies offer valuable insights into drug candidates and their interactions within intricate protein environments. This research lays a strategic foundation for targeted interventions against drug-resistant TB, highlighting ligand 2's potential for advanced drug development strategies."

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

Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis (clinicaltrials.gov) - P2 | N=93 | Completed | Sponsor: Bill & Melinda Gates Medical Research Institute | Phase classification: P2a ➔ P2

Phase classification • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

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

Discovery of N-(1-(6-Oxo-1,6-dihydropyrimidine)-pyrazole) Acetamide Derivatives as Novel Noncovalent DprE1 Inhibitors against Mycobacterium tuberculosis. (PubMed, J Med Chem) - "Among them, compounds LK-60 and LK-75 are capable of effectively suppressing the proliferation of Mtb with MIC values of 0.78-1.56 μM, comparable with isoniazid and much superior to the phase II candidate TBA-7371 (MIC = 12.5 μM). LK-60 is also the most active DprE1 inhibitor derived from CADD so far. Further studies confirmed their high affinity to DprE1, good safety profiles to gut microbiota and human cells, and synergy effects with either rifampicin or ethambutol, indicating their broad potential for clinical applications."

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

Mutations in Rv0678 Reduce Susceptibility of Mycobacterium tuberculosis to the DprE1 Inhibitor TBA-7371. (PubMed, Antimicrob Agents Chemother) - No abstract available

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

Pyrimidine derivatives with antitubercular activity. (PubMed, Eur J Med Chem) - "Small molecules with antitubercular activity containing the pyrimidine motif in their structure have gained more attention after three drugs, namely GSK 2556286 (GSK-286), TBA-7371 and SPR720, have entered clinical trials. In the first part, the review discusses the pyrimidine compounds according to their targets, pinpointing the structure-activity relationships of each pyrimidine family. The second part of this review is concentrated on antitubercular pyrimidine derivatives with a yet unexplored or speculative target, dividing the compounds according to their structural types."

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

Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis (clinicaltrials.gov) - P2a | N=93 | Completed | Sponsor: Bill & Melinda Gates Medical Research Institute | Recruiting ➔ Completed

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

Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis (clinicaltrials.gov) - P2a | N=90 | Recruiting | Sponsor: Bill & Melinda Gates Medical Research Institute | Trial completion date: Dec 2022 ➔ Aug 2022 | Trial primary completion date: Dec 2022 ➔ Aug 2022

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

Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis (clinicaltrials.gov) - P2a | N=90 | Recruiting | Sponsor: Bill & Melinda Gates Medical Research Institute | Trial completion date: Feb 2022 ➔ Dec 2022 | Trial primary completion date: Jan 2022 ➔ Dec 2022

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

Exploring targets of cell wall protein synthesis and overexpression mediated drug resistance for the discovery of potential M. tb inhibitors. (PubMed, Curr Top Med Chem) - "In addition, the compounds such as TBA-7371, TBI-166, AZD5847 and PBTZ-169 are under clinical trials whereas the recently FDA approved anti tubercular drugs are Pretomanid (PA-824), Bedaquiline (TMC207), Linezolid (PNU-100480) and Delamanid (OPC-67683). The early detection of mycobacterium tuberculosis can be permanently cured by DOTS comprising of Pyrazinamide (Z), Isoniazid (H), Rifampin (R) and Ethambutol (E)...Overexpression of these genes may produce drug-resistant due to dose misuse or the intake of quality compromised anti tubercular drug regimen. Therefore, in the present review there has been a necessity to report the second line antitubercular chemotherapeutics to target various proteins which are the building block of M. tb cell wall, overexpression of which may produce drug resistance."

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

Comparative Analysis of Pharmacodynamics in the C3HeB/FeJ Mouse Tuberculosis Model for DprE1 inhibitors TBA-7371, PBTZ169 and OPC-167832. (PubMed, Antimicrob Agents Chemother) - "Superior efficacy was observed for OPC-167832 even at low dose levels, which can be attributed to its low MIC, favorable distribution and sustained retention above the MIC throughout the dosing interval in caseous necrotic lesions where the majority of bacteria reside in C3HeB/FeJ mice. These results support further progression of the three drug candidates through clinical development for tuberculosis treatment."

Journal • PK/PD data • Preclinical • Infectious Disease • Pulmonary Disease • Respiratory Diseases • Tuberculosis

Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis (clinicaltrials.gov) - P2a; N=90; Recruiting; Sponsor: Bill & Melinda Gates Medical Research Institute; Trial completion date: Dec 2020 ➔ Feb 2022; Trial primary completion date: Dec 2020 ➔ Jan 2022

Clinical • Trial completion date • Trial primary completion date • Infectious Disease • Respiratory Diseases • Tuberculosis

Structure based pharmacophore modelling approach for the design of azaindole derivatives as DprE1 inhibitors for tuberculosis. (PubMed, J Mol Graph Model) - "TBA7371 (azaindole derivative, non-covalent inhibitor) is currently in first phase of clinical trials as DprE1 inhibitor. Azaindoles have been found to be equally potent against drug-sensitive and isoniazid/rifampin-resistant strains...All the results obtained from our study were interpreted and compared with DprE1 inhibitor in clinical trials. Study identified ZINC000170252277 as a potential hit compound for further biological evaluation as DprE1 inhibitor."

Journal • Human Immunodeficiency Virus • Infectious Disease • Tuberculosis

Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis (clinicaltrials.gov) - P2a; N=90; Recruiting; Sponsor: Bill & Melinda Gates Medical Research Institute; Suspended ➔ Recruiting

Clinical • Enrollment open • Infectious Disease • Tuberculosis • F2

Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis (clinicaltrials.gov) - P2a; N=90; Suspended; Sponsor: Bill & Melinda Gates Medical Research Institute; Recruiting ➔ Suspended

Clinical • Trial suspension • F2

Early Bactericidal Activity of TBA-7371 in Pulmonary Tuberculosis (clinicaltrials.gov) - P2a; N=90; Recruiting; Sponsor: Bill & Melinda Gates Medical Research Institute; Not yet recruiting ➔ Recruiting

Clinical • Enrollment open