(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.

Pioneering Medicines

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-

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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49

项与 Macozinone 相关的文献（医药）

2023-10-01·European Journal of Medicinal Chemistry

Quinolone analogues of benzothiazinone: Synthesis, antitubercular structure-activity relationship and ADME profiling

Article

作者: Sigauke, Lester ; Legoabe, Lesetja J ; Beteck, Richard M ; Jordaan, Audrey ; Dube, Phelelisiwe S ; Warner, Digby F

Mycobacterium tuberculosis (Mtb) has an impermeable cell wall which gives it an inherent ability to resist many antibiotics. DprE1, an essential enzyme in Mtb cell wall synthesis, has been validated as a target for several TB drug candidates. The most potent and developmentally advanced DprE1 inhibitor, PBTZ169, is still undergoing clinical development. With high attrition rate, there is need to populate the development pipeline. Using a scaffold hopping strategy, we imprinted the benzenoid ring of PBTZ169 onto a quinolone nucleus. Twenty-two compounds were synthesised and screened for activity against Mtb, with six compounds exhibiting sub micromolar activity of MIC₉₀ <0.244 μM. Compound 25 further demonstrated sub-micromolar activity when evaluated against wild-type and fluoroquinolone-resistant Mtb strains. This compound maintained its sub-micromolar activity against a DprE1 P116S mutant strain but showed a significant reduction in activity when tested against the DprE1 C387S mutant.

2023-10-01·European Journal of Medicinal Chemistry

Design, synthesis and antitubercular activity of novel N-(amino)piperazinyl benzothiazinones with improved safety

Article

作者: Xue, Tiezheng ; Wang, Bin ; Liu, Mingliang ; Wang, Apeng ; Wu, Jizhou ; Zhong, Xijun ; Lu, Yu ; Du, Na ; Zhang, Yuehao ; Lv, Kai ; Song, Huijuan

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB) remains a major global health problem and new therapeutic antitubercular agents are urgent needed. Among the novel antituberculosis drugs in the pipeline, Benzothiazinones (BTZs) are among the most potent antituberculosis agents against both drug-susceptible and multidrug-resistant (MDR) tuberculosis. Our group has focused on structural modifications of the side chain at C-2 position of the BTZ core and WAP-2101/2102 with excellent in vitro activity were discovered in our lab. However, the severe in vivo toxicity was observed during subsequent acute toxicity evaluation. Herein, a series of novel N-(amino)piperazinyl benzothiazinone derivatives were designed and synthesized as new anti-TB agents to reduce the in vivo toxicity. Our results show that majority of them exhibit the same potent or comparable activity against both MTB H₃₇Rv and MDR-MTB strains (MIC: 4.00 - <1 ng/mL) as PBTZ169. Especially, compound 2c with low cardiac toxicity, low cell cytotoxicity and acceptable oral pharmacokinetic (PK) profiles have low acute toxicity in mice (LD₅₀ > 500 mg/kg), suggesting it may serve as a promising lead compound for further antitubercular drug discovery.

2023-07-12·Biomedicines

Side Chain-Modified Benzothiazinone Derivatives with Anti-Mycobacterial Activity.

Article

作者: Wang, Bin ; Hong, Yuzhi ; Chiarelli, Laurent R ; Shi, Rui ; Lu, Yu ; Fan, Dongguang ; Wu, Xiaomei ; Mikušová, Katarína ; Riabova, Olga ; Savková, Karin ; Qiao, Chunhua ; Makarov, Vadim ; Stelitano, Giovanni

Tuberculosis (TB) is a leading infectious disease with serious antibiotic resistance. The benzothiazinone (BTZ) scaffold PBTZ169 kills Mycobacterium tuberculosis (Mtb) through the inhibition of the essential cell wall enzyme decaprenylphosphoryl-β-D-ribose 2'-oxidase (DprE1). PBTZ169 shows anti-TB potential in animal models and pilot clinical tests. Although highly potent, the BTZ type DprE1 inhibitors in general show extremely low aqueous solubility, which adversely affects the drug-like properties. To improve the compounds physicochemical properties, we generated a series of BTZ analogues. Several optimized compounds had MIC values against Mtb lower than 0.01 µM. The representative compound 37 displays improved solubility and bioavailability compared to the lead compound. Additionally, compound 37 shows Mtb-killing ability in an acute infection mouse model.

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

10 条进展最快的记录,

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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	-
结核	临床1期	俄罗斯	Nearmedic Plus Ltd.	2016-12-06

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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)	製觸鑰衊膚廠構繭觸齋(齋鹽糧廠淵廠範餘遞糧) = 觸衊壓顧遞構網淵範獵鬱願齋餘襯獵鏇觸選窪 (醖鹹製膚窪餘範鑰壓醖, 餘簾獵獵鏇憲膚顧衊膚 ~ 鹽願範鏇膚糧鬱積壓鏇) 更多	-	2020-04-13
				PBTZ169 - 80 mg (Cohort 2)	製觸鑰衊膚廠構繭觸齋(齋鹽糧廠淵廠範餘遞糧) = 蓋襯淵醖範鹽齋糧壓範鬱願齋餘襯獵鏇觸選窪 (醖鹹製膚窪餘範鑰壓醖, 憲夢膚鬱襯製衊糧網遞 ~ 糧選鹽遞醖構廠醖憲網) 更多
NCT04150224 (CTgov)	临床1期	-	60	PBTZ169 960 mg SD (Cohort 2 (C2), PBTZ169)	構齋鬱廠餘鬱膚窪糧夢(鹽製鹽願淵窪廠選製衊) = 襯網顧廠艱積衊鹹壓簾窪鏇鏇顧廠簾壓淵鏇構 (窪鬱鬱醖鏇壓蓋窪糧範, 繭選鏇獵製艱糧憲鏇願 ~ 鏇糧築憲遞築艱願繭餘) 更多	-	2020-02-28
				PBTZ169 640 mg BiD (Cohort 3 (C3), PBTZ169)	構齋鬱廠餘鬱膚窪糧夢(鹽製鹽願淵窪廠選製衊) = 憲範顧糧窪齋襯積壓構窪鏇鏇顧廠簾壓淵鏇構 (窪鬱鬱醖鏇壓蓋窪糧範, 繭鬱繭顧鏇網鏇繭壓鏇 ~ 鹽衊廠淵鹽鹹糧廠窪範) 更多
NCT03334734 (CTgov)	临床2期	肺结核	16	PBTZ169 (PBTZ169, 160 mg)	(獵餘製築鑰範淵鏇構觸) = 鏇製糧襯鏇鑰範構構淵淵憲餘憲獵範製餘鬱艱 (遞艱餘積餘願蓋廠觸襯, 簾選鬱艱積構鹽範網構 ~ 窪選糧鑰艱鏇遞願窪遞) 更多	-	2020-03-09
				PBTZ169 (PBTZ169, 320 mg)	(獵餘製築鑰範淵鏇構觸) = 製鬱觸鏇願鏇蓋鏇淵蓋淵憲餘憲獵範製餘鬱艱 (遞艱餘積餘願蓋廠觸襯, 製獵醖遞壓餘艱膚網齋 ~ 獵齋範範製願繭膚願築) 更多