Macozinone(Macozinone) - 药物靶点：DprE1_在研适应症：肺结核_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

DprE1

作用机制

DprE1抑制剂(FAD依赖性十聚丙烯基磷酰基-β-D-呋喃核糖二氧化酶抑制剂)

治疗领域

感染呼吸系统疾病

在研适应症

肺结核

非在研适应症-

原研机构

École Polytechnique Fédérale de Lausanne

在研机构

École Polytechnique Fédérale de Lausanne

非在研机构

Nearmedic Plus Ltd.

最高研发阶段临床2期

首次获批日期-

最高研发阶段(中国)-

特殊审评-

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结构

分子式C20H23F3N4O3S

InChIKeyBJDZBXGJNBMCAV-UHFFFAOYSA-N

CAS号1377239-83-2

关联

5

项与 Macozinone 相关的临床试验

NCT03776500 / Completed临床1期

Safety, Tolerability and Pharmacokinetic Profile of PBTZ169 Formulated as Native Crystal Powder: Multiple Ascending Doses, Randomized, Placebo- Controlled, Parallel-group, Sequential Phase Ib Trial in Healthy Volunteers

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

开始日期2019-02-21

申办/合作机构

Pioneering Medicines

[+1]

NCT04150224 / Completed临床1期

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

开始日期2018-07-03

申办/合作机构

Nearmedic Plus Ltd.

NCT03423030 / Completed临床1期

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.

开始日期2017-12-05

申办/合作机构

Pioneering Medicines

[+1]

100 项与 Macozinone 相关的临床结果

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100 项与 Macozinone 相关的转化医学

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100 项与 Macozinone 相关的专利（医药）

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54

项与 Macozinone 相关的文献（医药）

2024-12-01·European Journal of Medicinal Chemistry

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

Article

作者: 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.

2024-07-02·ACS Omega

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

Article

作者: 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.

2024-06-01·Microbes and Infection

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

Article

作者: 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 项与 Macozinone 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14821

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
肺结核	临床2期	-	École Polytechnique Fédérale de Lausanne	-

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临床结果

适应症

分期

评价

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03036163 (CTgov)	临床1期	结核	40	PBTZ169 - 40 mg (Cohort 1)	製衊襯選淵壓繭顧選憲(襯築遞繭夢鏇鑰鑰繭齋) = 遞製鹽蓋憲淵廠網夢繭蓋網遞構廠壓範鏇膚淵 (範築獵構築淵襯遞糧蓋, 網醖簾遞壓製顧鏇壓壓 ~ 糧範壓獵願鏇艱淵蓋夢) 更多	-	2020-04-13
				PBTZ169 - 80 mg (Cohort 2)	製衊襯選淵壓繭顧選憲(襯築遞繭夢鏇鑰鑰繭齋) = 夢積鹽廠窪襯夢選積顧蓋網遞構廠壓範鏇膚淵 (範築獵構築淵襯遞糧蓋, 糧窪簾艱遞鬱築觸壓廠 ~ 壓廠鑰膚鹹糧網鹽鏇簾) 更多
NCT03334734 (CTgov)	临床2期	肺结核	16	PBTZ169 (PBTZ169, 160 mg)	膚壓積衊夢選網餘襯築(觸範衊膚艱構蓋淵範觸) = 築獵製蓋窪構夢繭築構構鬱齋繭鹽鏇鑰簾築餘 (製鹽衊壓構蓋範範獵積, 構蓋鬱襯鹹膚餘衊衊製 ~ 獵觸網憲鹽蓋顧繭糧艱) 更多	-	2020-03-09
				PBTZ169 (PBTZ169, 320 mg)	膚壓積衊夢選網餘襯築(觸範衊膚艱構蓋淵範觸) = 糧衊遞鹽壓觸鑰蓋構壓構鬱齋繭鹽鏇鑰簾築餘 (製鹽衊壓構蓋範範獵積, 範鏇網醖鹹壓顧遞蓋醖 ~ 壓選鏇遞窪蓋膚觸糧獵) 更多
NCT04150224 (CTgov)	临床1期	-	60	PBTZ169 960 mg SD (Cohort 2 (C2), PBTZ169)	選鏇糧築鬱積獵艱壓鏇(鏇廠憲窪鬱鹹憲齋蓋觸) = 糧構廠積鏇簾膚觸壓醖襯齋淵夢遞糧顧繭蓋鑰 (積膚壓憲窪淵鑰夢壓鏇, 簾淵糧壓廠獵築鹹築願 ~ 醖廠糧鑰淵醖鏇繭範艱) 更多	-	2020-02-28
				PBTZ169 640 mg BiD (Cohort 3 (C3), PBTZ169)	選鏇糧築鬱積獵艱壓鏇(鏇廠憲窪鬱鹹憲齋蓋觸) = 觸簾遞願窪繭醖廠壓窪襯齋淵夢遞糧顧繭蓋鑰 (積膚壓憲窪淵鑰夢壓鏇, 衊選簾餘繭衊蓋窪淵艱 ~ 衊鹽遞鬱觸獵願憲淵齋) 更多