LYS-006(LYS-006) - 药物靶点：LTA4H_专利_临床

概要

基本信息

药物类型

小分子化药

别名

靶点

LTA4H

作用机制

LTA4H抑制剂(白三烯A4水解酶抑制剂)

治疗领域

免疫系统疾病消化系统疾病皮肤和肌肉骨骼疾病

在研适应症-

非在研适应症

寻常痤疮溃疡性结肠炎

原研机构

Novartis Pharma AG

在研机构-

非在研机构

Novartis Pharmaceuticals Corp.

最高研发阶段终止临床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C16H14ClFN6O3

InChIKeyZEGMEJVULDALSH-NSHDSACASA-N

CAS号1799681-85-8

关联

5

项与 LYS-006 相关的临床试验

JPRN-jRCT2051200111 / Completed临床1期IIT

A randomized, participant-blinded and investigator-partial blinded, placebo-controlled, and single ascending dose study to assess the safety, tolerability and pharmacokinetics of LYS006 in Japanese healthy male participants

开始日期2021-01-30

申办/合作机构-

NCT04147195 / Terminated临床2期

NASH EXploratory Single and COmbination Treatment (NEXSCOT): An Open Label, Multicenter, Platform Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Efficacy of Various Single and Combination Treatments in Patients With Non-alcoholic Fatty Liver Disease (NAFLD) Who Manifest a Non-alcoholic Steatohepatitis (NASH)-Like Biomarker Phenotype

This clinical study was designed to evaluate the safety, tolerability, pharmacokinetics and efficacy of various single and combination treatments in adult patients with non-alcoholic fatty liver disease (NAFLD) who manifest a non-alcoholic steatohepatitis (NASH)-like biomarker phenotype.

开始日期2020-06-04

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT04074590 / Terminated临床2期

A Randomized, Multi-center, Subject and Investigator-blinded, Placebo-controlled, Parallel-group Study to Assess the Efficacy Safety and Tolerability of LYS006 in Patients With Mild to Moderate Ulcerative Colitis

The purpose of the study was to assess preliminary efficacy, safety, and tolerability of LYS006 in adult patients with mild to moderate ulcerative colitis and to determine if LYS006 has an adequate clinical profile for further development in this indication.

开始日期2020-02-03

申办/合作机构

Novartis Pharmaceuticals Corp.

100 项与 LYS-006 相关的临床结果

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100 项与 LYS-006 相关的转化医学

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100 项与 LYS-006 相关的专利（医药）

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3

项与 LYS-006 相关的文献（医药）

2024-02-01·Clinical and Translational Science

LTA4H inhibitor LYS006: Clinical PK/PD and safety in a randomized phase I clinical trial

Article

作者: Jäger, Petra ; Fink, Martin ; Otto, Heike ; Weiss, H. Markus ; Loesche, Christian ; Schuhler, Carole ; Picard, Damien ; Thoma, Gebhard ; Markert, Christian ; Klein, Kai ; Poller, Birk ; Schuhmann, Imelda ; Van Hoorick, Benjamin ; Zamurovic, Natasa ; Röhn, Till A.

AbstractLYS006 is a novel, highly potent and selective, new‐generation leukotriene A4 hydrolase (LTA4H) inhibitor in clinical development for the treatment of neutrophil‐driven inflammatory diseases. We describe the complex pharmacokinetic to pharmacodynamic (PD) relationship in blood, plasma, and skin of LYS006‐treated nonclinical species and healthy human participants. In a randomized first in human study, participants were exposed to single ascending doses up to 100 mg and multiple ascending doses up to 80 mg b.i.d.. LYS006 showed rapid absorption, overall dose proportional plasma exposure and nonlinear blood to plasma distribution caused by saturable target binding. The compound efficiently inhibited LTB4 production in human blood and skin blister cells, leading to greater than 90% predose target inhibition from day 1 after treatment initiation at doses of 20 mg b.i.d. and above. Slow re‐distribution from target expressing cells resulted in a long terminal half‐life and a long‐lasting PD effect in ex vivo stimulated blood and skin cells despite low plasma exposures. LYS006 was well‐tolerated and demonstrated a favorable safety profile up to highest doses tested, without any dose‐limiting toxicity. This supported further clinical development in phase II studies in predominantly neutrophil‐driven inflammatory conditions, such as hidradenitis suppurativa, inflammatory acne, and ulcerative colitis.

2023-12-14·Journal of Medicinal Chemistry1区 · 医学

Discovery of Amino Alcohols as Highly Potent, Selective, and Orally Efficacious Inhibitors of Leukotriene A4 Hydrolase

1区 · 医学

Article

作者: Thoma, Gebhard ; Penno, Carlos A ; Miltz, Wolfgang ; Gajewska, Monika ; Markert, Christian ; Beerli, Christian ; Bollbuck, Birgit ; Bednarczyk, Dallas ; Spanka, Carsten ; Röhn, Till A ; Evans, Amanda ; Srinivas, Honnappa ; Wieczorek, Grazyna ; Wolf, Romain M ; Lueoend, Rainer ; Kiffe, Michael

The discovery of chiral amino alcohols derived from our previously disclosed clinical LTA4H inhibitor LYS006 is described. In a biochemical assay, their optical antipodes showed similar potencies, which could be rationalized by the cocrystal structures of these compounds bound to LTA4H. Despite comparable stabilities in liver microsomes, they showed distinct in vivo PK properties. Selective O-phosphorylation of the (R)-enantiomers in blood led to clearance values above the hepatic blood flow, whereas the (S)-enantiomers were unaffected and exhibited satisfactory metabolic stabilities in vivo. Introduction of two pyrazole rings led to compound (S)-2 with a more balanced distribution of polarity across the molecule, exhibiting high selectivity and excellent potency in vitro and in vivo. Furthermore, compound (S)-2 showed favorable profiles in 16-week IND-enabling toxicology studies in dogs and rats. Based on allometric scaling and potency in whole blood, compound (S)-2 has the potential for a low oral efficacious dose administered once daily.

2021-02-25·Journal of Medicinal Chemistry1区 · 医学

Discovery of LYS006, a Potent and Highly Selective Inhibitor of Leukotriene A₄ Hydrolase

1区 · 医学

Article

作者: Hinrichs, Jurgen ; Rohn, Till A. ; Klein, Kai ; Penno, Carlos A. ; Beerli, Christian ; Loetscher, Pius ; Littlewood-Evans, Amanda ; Thoma, Gebhard ; Miltz, Wolfgang ; Wack, Nathalie ; Numao, Shin ; Srinivas, Honnappa ; Dawson, Janet ; Wolf, Romain ; Markert, Christian ; Bergsdorf, Christian ; Jager, Petra ; Hasler, Franziska ; Azzaoui, Kamal ; Walchli, Rudolf ; Luond, Rainer M. ; Wieczorek, Grazyna ; Bollbuck, Birgit

The cytosolic metalloenzyme leukotriene A₄ hydrolase (LTA4H) is the final and rate-limiting enzyme in the biosynthesis of pro-inflammatory leukotriene B₄ (LTB₄). Preclinical studies have validated this enzyme as an attractive drug target in chronic inflammatory diseases. Despite several attempts, no LTA4H inhibitor has reached the market, yet. Herein, we disclose the discovery and preclinical profile of LYS006, a highly potent and selective LTA4H inhibitor. A focused fragment screen identified hits that could be cocrystallized with LTA4H and inspired a fragment merging. Further optimization led to chiral amino acids and ultimately to LYS006, a picomolar LTA4H inhibitor with exquisite whole blood potency and long-lasting pharmacodynamic effects. Due to its high selectivity and its ability to fully suppress LTB₄ generation at low exposures in vivo, LYS006 has the potential for a best-in-class LTA4H inhibitor and is currently investigated in phase II clinical trials in inflammatory acne, hidradenitis suppurativa, ulcerative colitis, and NASH.

100 项与 LYS-006 相关的药物交易

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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
溃疡性结肠炎	临床2期	波兰	Novartis Pharmaceuticals Corp.	2020-02-03
溃疡性结肠炎	临床2期	保加利亚	Novartis Pharmaceuticals Corp.	2020-02-03
溃疡性结肠炎	临床2期	斯洛伐克	Novartis Pharmaceuticals Corp.	2020-02-03
溃疡性结肠炎	临床2期	德国	Novartis Pharmaceuticals Corp.	2020-02-03
寻常痤疮	临床2期	法国	Novartis Pharmaceuticals Corp.	2018-09-10
寻常痤疮	临床2期	荷兰	Novartis Pharmaceuticals Corp.	2018-09-10
寻常痤疮	临床2期	美国	Novartis Pharmaceuticals Corp.	2018-09-10
寻常痤疮	临床2期	捷克	Novartis Pharmaceuticals Corp.	2018-09-10
寻常痤疮	临床2期	德国	Novartis Pharmaceuticals Corp.	2018-09-10
寻常痤疮	临床2期	匈牙利	Novartis Pharmaceuticals Corp.	2018-09-10

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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


NCT04074590 (CTgov)	临床2期	溃疡性结肠炎	23	Placebo	顧膚製繭齋鑰鹹網鹹積(顧夢憲廠襯築糧觸積廠) = 艱糧範憲構夢遞遞選憲糧淵築夢窪鏇夢鏇淵願 (積繭淵遞選鹹鹹鑰鑰鹽, 顧蓋蓋遞網衊製鹽憲觸 ~ 選鏇構齋網鏇壓製窪製) 更多	-	2023-11-09
NCT03497897 (CTgov)	临床2期	寻常痤疮	66	LYS006 20 mg (LYS006 20 mg BID)	範鑰顧衊糧遞願淵糧獵(簾簾餘憲遞範簾糧膚獵) = 艱鹽獵積膚鑰蓋糧製憲鏇鬱鹹鑰襯構範醖構憲 (網網獵簾鑰夢蓋積繭遞, 餘鬱範鬱廠廠鹽範願窪 ~ 築餘淵淵壓積遞觸鹽網) 更多	-	2023-03-20
				LYS006 2 mg (LYS006 2 mg BID)	範鑰顧衊糧遞願淵糧獵(簾簾餘憲遞範簾糧膚獵) = 鏇選衊淵餘艱醖衊襯窪鏇鬱鹹鑰襯構範醖構憲 (網網獵簾鑰夢蓋積繭遞, 艱積餘蓋齋選蓋糧餘膚 ~ 積選遞選範選餘齋製膚) 更多
NCT04147195 (CTgov)	临床2期	非酒精性脂肪性肝炎	41	LYS006 (LYS006)	(壓襯網淵範顧遞簾餘蓋) = 簾繭壓遞網範範餘觸構簾壓鏇齋糧窪築鑰觸構 (衊醖築範選餘構蓋顧窪, 衊鹽鏇衊鹹齋鬱鑰積願 ~ 選膚窪齋願製鬱衊獵繭) 更多	-	2023-01-26
				Tropifexor (LYS006 + LJN452)	(壓襯網淵範顧遞簾餘蓋) = 構簾壓觸餘顧顧憲鹽醖簾壓鏇齋糧窪築鑰觸構 (衊醖築範選餘構蓋顧窪, 網網範觸齋齋構膚築獵 ~ 醖顧廠築獵選遞憲積淵) 更多