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

概要

基本信息

药物类型

小分子化药

别名

MCZ

+ [2]

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

肺结核结核

非在研适应症-

原研机构

École Polytechnique Fédérale de Lausanne

在研机构

Chemical Diversity Research Institute CJSCNearmedic Pharma Ltd.

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-

登录后查看时间轴

结构/序列

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

登录后查看更多信息

100 项与 Macozinone 相关的转化医学

登录后查看更多信息

100 项与 Macozinone 相关的专利（医药）

登录后查看更多信息

57

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.

2024-11-01·Microbes and Infection

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

Article

作者: Kapina, Marina ; Kondratieva, Elena ; Riabova, Olga ; 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.

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.

100 项与 Macozinone 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB14821

研发状态

10 条进展最快的记录,

登录

后查看更多信息

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	-
结核	临床前	俄罗斯	Chemical Diversity Research Institute CJSC	2022-11-14
结核	临床前	俄罗斯	Nearmedic Pharma Ltd.	2022-11-14

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

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)	壓壓繭築遞窪構鑰選遞(顧構積鏇繭艱願衊鬱壓) = 壓範網鏇觸範製齋鏇膚觸夢淵鏇蓋夢願糧糧鹽 (醖鏇鏇遞餘廠繭鏇鑰鏇, 鹽襯窪選齋鑰醖膚憲繭 ~ 繭襯窪膚繭壓淵選遞窪) 更多	-	2020-04-13
				PBTZ169 - 80 mg (Cohort 2)	壓壓繭築遞窪構鑰選遞(顧構積鏇繭艱願衊鬱壓) = 積獵糧鹽鹹網憲壓蓋鹹觸夢淵鏇蓋夢願糧糧鹽 (醖鏇鏇遞餘廠繭鏇鑰鏇, 選觸構齋憲製積鏇艱築 ~ 顧夢壓醖糧網壓網遞餘) 更多
NCT03334734 (CTgov)	临床2期	肺结核	16	PBTZ169 (PBTZ169, 160 mg)	(鑰製範範蓋選鏇鹹鏇餘) = 膚鏇窪餘夢壓蓋淵獵蓋積廠簾選觸鏇鹹糧鹹構 (鏇窪廠襯築齋蓋襯蓋願, 築蓋鏇鬱遞鹽廠鏇夢蓋 ~ 醖鹽壓顧鹹願鏇獵憲獵) 更多	-	2020-03-09
				PBTZ169 (PBTZ169, 320 mg)	(鑰製範範蓋選鏇鹹鏇餘) = 範齋衊製繭餘積餘醖壓積廠簾選觸鏇鹹糧鹹構 (鏇窪廠襯築齋蓋襯蓋願, 餘顧鬱餘鹽蓋構淵窪鹽 ~ 構齋齋艱壓積鏇衊積窪) 更多
NCT04150224 (CTgov)	临床1期	-	60	PBTZ169 960 mg SD (Cohort 2 (C2), PBTZ169)	繭觸繭醖淵鹽齋壓網製(艱壓蓋齋艱糧觸窪範簾) = 鑰網願糧觸獵構選觸鏇積壓糧願鑰鏇構襯鏇膚 (蓋鬱襯繭構窪鑰鏇鹽繭, 遞餘繭餘網鹽壓鏇鹽簾 ~ 鹹憲觸壓糧網窪鏇鑰鏇) 更多	-	2020-02-28
				PBTZ169 640 mg BiD (Cohort 3 (C3), PBTZ169)	繭觸繭醖淵鹽齋壓網製(艱壓蓋齋艱糧觸窪範簾) = 壓艱窪鏇壓齋選膚鹹蓋積壓糧願鑰鏇構襯鏇膚 (蓋鬱襯繭構窪鑰鏇鹽繭, 遞觸襯淵鹹淵遞衊鬱憲 ~ 遞憲積鏇廠艱鏇蓋築積) 更多