Delving into the Latest Updates on Macozinone with Synapse

Overview

Basic Info

Drug Type

Small molecule drug

Synonyms

Target

DprE1

Mechanism

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

Therapeutic Areas

Infectious DiseasesRespiratory Diseases

Active Indication

Pulmonary Tuberculosis

Inactive Indication-

Originator Organization

École Polytechnique Fédérale de Lausanne

Active Organization

École Polytechnique Fédérale de Lausanne

Inactive Organization

Nearmedic Plus Ltd.

Drug Highest PhasePhase 2

First Approval Date-

Regulation-

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Structure

Molecular FormulaC20H23F3N4O3S

InChIKeyBJDZBXGJNBMCAV-UHFFFAOYSA-N

CAS Registry1377239-83-2

This is a randomized, double-blind, placebo-controlled, multiple ascending dose study conducted at one study center in Switzerland.
Four (4) panels (A, B, C and D) of 8 male subjects (6 active and 2 placebo) each receiving multiple doses of PBTZ169 or a matching placebo, at increasing dose levels, once or twice daily.
Subjects will participate in only one panel. Blocks of 4 subjects (3 under active treatment, 1 under placebo) will be investigated in parallel. Panels will start sequentially.
Safety will be assessed throughout the study; serial ECGs and serial blood samples will be collected for the safety and PK assessment of PBTZ169.
Dose escalation will be allowed once the Trial Safety Board has determined that adequate safety and tolerability after each panel completion has been demonstrated to permit proceeding to the next panel.
In addition, a preliminary assessment of the drug interaction potential of PBTZ169 will be done by the measurement of inhibition or induction of human cytochromes through the metabolism of microdoses of standard probe substrates

Start Date21 Feb 2019

Sponsor / Collaborator

Pioneering Medicines

[+1]

NCT04150224 / CompletedPhase 1

An Open-label, Prospective Study of Safety, Tolerability, Pharmacokinetics and Food Effects of PBTZ169, 80 mg Capsules, When Used in Ascending Doses in Healthy Volunteers

Open-label prospective non-comparative ascending dose randomized cohort study of single and multiple oral administration of PBTZ169 (capsules 80 mg) in healthy volunteers

Start Date03 Jul 2018

Sponsor / Collaborator

Nearmedic Plus Ltd.

NCT03423030 / CompletedPhase 1

Safety, Tolerability, Pharmacokinetic Profile and Ex-vivo Antitubercular Activity of PBTZ169 Formulated as Spray- Dried Dispersion Versus Native Crystal Powder: Single Ascending Doses, Randomized, Placebo- Controlled, Cross-over Phase Ia Trial in Healthy Volunteers

This is a randomized, double-blind, placebo-controlled, single ascending dose study conducted at one study center in Switzerland.
Four (4) panels (A, B, C and D) of 8 male subjects (6 active and 2 placebo) each undergoing 2 investigation periods and receiving either single doses of PBTZ169 at increasing dose levels or a matching placebo.
Subjects will participate in only one panel. Blocks of 4 subjects (3 under active treatment, 1 under placebo) will be investigated in parallel. Panels A and B are interleaved.
Safety will be assessed throughout the study; serial ECGs and serial blood samples will be collected for the safety and PK assessment of PBTZ169.
Dose escalation will be allowed once the Trial Safety Board has determined that adequate safety and tolerability after panel B and panel C completion has been demonstrated to permit proceeding to the next panel.

Start Date05 Dec 2017

Sponsor / Collaborator

Pioneering Medicines

[+1]

100 Clinical Results associated with Macozinone

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100 Translational Medicine associated with Macozinone

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100 Patents (Medical) associated with Macozinone

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54

Literatures (Medical) associated with Macozinone

01 Dec 2024·European Journal of Medicinal Chemistry

Design, synthesis and antimycobacterial activity of novel benzothiazinones with improved water solubility

Article

Author: Zhong, Xijun ; Lv, Kai ; Xue, Tiezheng ; gong, Jiaqi ; Ma, Chao ; Wang, Apeng ; Zhou, Sheng ; Wei, Meng ; Wang, Bin ; Wu, Jizhou ; Gong, Jiaqi ; Liu, Mingliang ; Lu, Yu ; Du, Na

Nitrobenzothiazinones (BTZs) represent a novel type of antitubercular agents targeting DprE1. Two clinical candidates BTZ043 and PBTZ169, as well as many other BTZs showed potent anti-TB activity, but they are all highly lipophilic and their poor aqueous solubility is still a serious issue need to be addressed. Here, we designed and synthesized a series of new BTZ derivatives, wherein a hydrophilic COOH or NH₂ group is directly attached to the oxime moiety of TZY-5-84 discovered in our lab, through various linkers. Two compounds 1a and 3 were first reported to possess excellent activity against MTB H₃₇Rv and MDR-MTB strains (MIC: <0.029-0.095 μM), low toxicity and acceptable oral PK profiles, as well as significantly improved water solubility (1200 and > 2000 μg/mL, respectively), suggesting they may serve as promising hydrophilic BTZs for further antitubercular drug discovery.

02 Jul 2024·ACS Omega

Identifying Novel Therapeutics for the Resistant Mutant “F533L” in PBP3 of Pseudomonas aeruginosa Using ML Techniques

Article

Author: Anbarasu, Anand ; Vijayakumar, Santhiya ; Ghosh, Soumyadip ; Ramaiah, Sudha ; Mathpal, Shalini ; Joshi, Tushar

Pseudomonas aeruginosa (P. aeruginosa) is a highly infectious and antibiotic-resistant bacterium, which causes acute and chronic nosocomial infections. P. aeruginosa exhibits multidrug resistance due to the emergence of resistant mutants. The bacterium takes advantage of intrinsic and acquired resistance mechanisms to resist almost every antibiotic. To overcome the drug-resistance problem, there is a need to develop effective drugs against antibiotic-resistant mutants. Therefore, in this study, we selected the F533L mutation in PBP3 (penicillin-binding protein 3) because of its important role in β-lactam recognition. To target this mutation, we screened 147 antibacterial compounds from PubChem through a machine-learning model developed based on the decision stump algorithm with 75.75% accuracy and filtered out 55 compounds. Subsequently, out of 55 compounds, 47 compounds were filtered based on their drug-like activity. These 47 compounds were subjected to virtual screening to obtain binding affinity compounds. The binding affinity range of all 47 compounds was -11.3 to -4.6 kcal mol^-1. The top 10 compounds were examined according to their binding with the mutation point. A molecular dynamic simulation of the top 8 compounds was conducted to understand the stability of the compounds containing the mutated PBP3. Out of 8 compounds, 3 compounds, namely, macozinone, antibacterial agent 71, and antibacterial agent 123, showed good stability and were validated by RMSD, RMSF, and binding-free analysis. The findings of this study revealed promising antibacterial compounds against the F533L mutant PBP3. Furthermore, developments in these compounds may pave the way for novel therapeutic interventions.

01 Jun 2024·Microbes and Infection

Efficacy of macozinone in mice with genetically diverse susceptibility to Mycobacterium tuberculosis infection

Article

Author: Kondratieva, Elena ; Riabova, Olga ; Kapina, Marina ; Bocharova, Irina ; Semyonova, Lyudmila ; Makarov, Vadim ; Logunova, Nadezhda ; Nikonenko, Boris ; Sterzhanova, Natalia ; Egorova, Anna

Host heterogeneity in pulmonary tuberculosis leads to varied responses to infection and drug treatment. The present portfolio of anti-TB drugs needs to be boosted with new drugs and drug regimens. Macozinone, a clinical-stage molecule targeting the essential enzyme, DprE1, represents an attractive option. Mice (I/St, B6, (AKRxI/St)F1, B6.I-100 and B6.I-139) genetically diverse susceptibility to Mycobacterium tuberculosis (Mtb) H37Rv infection were subjected to aerosol- or intravenous infection to determine the efficacy of macozinone (MCZ). They were treated with macozinone or reference drugs (isoniazid, rifampicin). Lung and spleen bacterial burdens were measured at four and eight weeks post-infection. Lung histology was evaluated at four weeks of treatment. Treatment with macozinone resulted in a statistically significant reduction in the bacterial load in the lungs and spleen as early as four weeks after treatment initiation in mice susceptible or resistant to Mtb infection. In the TB hypoxic granuloma model, macozinone was more potent than rifampicin in reducing the CFU counts. However, histopathological analysis revealed significant lung changes in I/St mice after eight weeks of treatment initiation. Macozinone demonstrated efficacy to varying degrees across all mouse models of Mtb infection used. These results should facilitate its further development and potential introduction into clinical practice.

100 Deals associated with Macozinone

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External Link

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14821

R&D Status

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Pulmonary Tuberculosis	Phase 2	-	École Polytechnique Fédérale de Lausanne	-

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Clinical Result

Indication

Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT03036163 (CTgov)	Phase 1	Tuberculosis	40	PBTZ169 - 40 mg (Cohort 1)	fyyqlwlxnj(mgmfcogpld) = tlocsgidjw iftvpkereh (mzxjnbfqgl, mzeffewgdr - unwypxnkgw) View more	-	13 Apr 2020
				PBTZ169 - 80 mg (Cohort 2)	fyyqlwlxnj(mgmfcogpld) = yykmfldykc iftvpkereh (mzxjnbfqgl, wleutoewvs - rzrydryubb) View more
NCT03334734 (CTgov)	Phase 2	Pulmonary Tuberculosis	16	PBTZ169 (PBTZ169, 160 mg)	qgoioifuda(zfjrmnyfxt) = ytkbahyicw ldoaxliien (wubrlohcyk, ifxittxioi - aibfdxlxyf) View more	-	09 Mar 2020
				PBTZ169 (PBTZ169, 320 mg)	qgoioifuda(zfjrmnyfxt) = yavkxrklxx ldoaxliien (wubrlohcyk, mfhsnuztbd - gfhvqsrcyq) View more
NCT04150224 (CTgov)	Phase 1	-	60	PBTZ169 960 mg SD (Cohort 2 (C2), PBTZ169)	wczqhgegxo(rcuvttrtwn) = bgqqycbmrv jvrhesfpzv (qwtbrxffii, iiwxhbbwed - sbxxuhctqi) View more	-	28 Feb 2020
				PBTZ169 640 mg BiD (Cohort 3 (C3), PBTZ169)	wczqhgegxo(rcuvttrtwn) = moivirykwc jvrhesfpzv (qwtbrxffii, oxjjotpyoy - igxpqylxly) View more