Delving into the Latest Updates on TBA-7371 with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

DprE1

Action

inhibitors

Mechanism

DprE1 inhibitors(FAD-dependent decaprenylphosphoryl-beta-D-ribofuranose 2-oxidase inhibitors)

Therapeutic Areas

Infectious DiseasesRespiratory Diseases

Active Indication

Pulmonary TuberculosisTuberculosis

Inactive Indication-

Originator Organization

AstraZeneca Pharmaceuticals Co. Ltd.

Active Organization

Global Alliance for TB Drug Development

AstraZeneca Pharmaceuticals Co. Ltd.

Foundation For Neglected Disease Research

+ [2]

Inactive Organization-

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure/Sequence

Molecular FormulaC18H21N5O3

InChIKeyVDRYGTNDKXIPSK-UHFFFAOYSA-N

CAS Registry1494675-86-3

ABSTRACTThe Mycobacterium cell wall is a capsule‐like structure comprising of various layers of biomolecules such as mycolic acid, peptidoglycans, and arabinogalactans, which provide the Mycobacteria a sort of cellular shield. Drugs like isoniazid, ethambutol, cycloserine, delamanid, and pretomanid inhibit cell wall synthesis by inhibiting one or the other enzymes involved in cell wall synthesis. Many enzymes present across these layers serve as potential targets for the design and development of newer anti‐TB drugs. Some of these targets are currently being exploited as the most druggable targets like DprE1, InhA, and MmpL3. Many of the anti‐TB agents present in clinical trials inhibit cell wall synthesis. The present article covers a systematic perspective of developing cell wall inhibitors targeting various enzymes involved in cell wall biosynthesis as potential drug candidates for treating Mtb infection.

03 Apr 2024·Antimicrobial Agents and Chemotherapy

Bactericidal and sterilizing activity of novel regimens combining bedaquiline or TBAJ-587 with GSK2556286 and TBA-7371 in a mouse model of tuberculosis

Article

Author: Barros-Aguirre, David ; Ballell, Lluís ; Li, Si-Yang ; Jimenez-Navarro, Elena ; Converse, Paul J ; Nuermberger, Eric L ; Mdluli, Khisimuzi ; Upton, Anna M ; Betoudji, Fabrice ; Soni, Heena ; Tyagi, Sandeep ; Fotouhi, Nader

ABSTRACTThe combination of bedaquiline, pretomanid, and linezolid (BPaL) has become a preferred regimen for treating multidrug- and extensively drug-resistant tuberculosis (TB). However, treatment-limiting toxicities of linezolid and reports of emerging bedaquiline and pretomanid resistance necessitate efforts to develop new short-course oral regimens. We recently found that the addition of GSK2556286 increases the bactericidal and sterilizing activity of BPa-containing regimens in a well-established BALB/c mouse model of tuberculosis. Here, we used this model to evaluate the potential of new regimens combining bedaquiline or the more potent diarylquinoline TBAJ-587 with GSK2556286 and the DprE1 inhibitor TBA-7371, all of which are currently in early-phase clinical trials. We found the combination of bedaquiline, GSK2556286, and TBA-7371 to be more active than the first-line regimen and nearly as effective as BPaL in terms of bactericidal and sterilizing activity. 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.

08 Feb 2024·Journal of Medicinal ChemistryQ1 · MEDICINE

Discovery of N-(1-(6-Oxo-1,6-dihydropyrimidine)-pyrazole) Acetamide Derivatives as Novel Noncovalent DprE1 Inhibitors against Mycobacterium tuberculosis

Q1 · MEDICINE

Article

Author: Alam, Md Shah ; Zhang, Tianyu ; Hou, Tingjun ; Kang, Yu ; Che, Jinxin ; Lu, Yang ; Dong, Xiaowu ; Li, Dan ; Lei, Yixuan ; Ma, WanLi ; Hu, Xueping ; Xu, Yaping ; Ye, Qing ; Xu, Ruolan ; Yang, Liu ; Chai, Xin

Decaprenylphosphoryl-β-d-ribose oxidase (DprE1) is a promising target for treating tuberculosis (TB). Currently, most novel DprE1 inhibitors are discovered through high-throughput screening, while computer-aided drug design (CADD) strategies are expected to promote the discovery process. In this study, with the aid of structure-based virtual screening and computationally guided design, a series of novel scaffold N-(1-(6-oxo-1,6-dihydropyrimidine)-pyrazole) acetamide derivatives with significant antimycobacterial activities were identified. Among them, compounds LK-60 and LK-75 are capable of effectively suppressing the proliferation of Mtb with MIC_Mtb values of 0.78-1.56 μM, comparable with isoniazid and much superior to the phase II candidate TBA-7371 (MIC_Mtb = 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.

100 Deals associated with TBA-7371

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB16243

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Tuberculosis	Phase 2	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Tuberculosis	Preclinical	United States	Colorado State University	25 Jul 2021

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT04176250 (CTgov)	Phase 2	Pulmonary Tuberculosis	93	TBA-7371 (TBA-7371 100 mg QD)	rcnpbdiqsd(qilodjzbkp) = ptpnkvnurv rcviwehbml (owvuykifno, kcvruswndu - terilxrbrt) View more	-	11 Apr 2024
				TBA-7371 (TBA-7371 100 mg BID)	rcnpbdiqsd(qilodjzbkp) = gjzmcqgqaf rcviwehbml (owvuykifno, rspevqvwyc - kovsysmtea) View more