更新于：2024-05-01

5-LOX

5-脂氧合酶

更新于：2024-05-01

基本信息

别名

花生四烯酸盐5-脂氧合酶、5-lipoxygenase、5-LO

+ [5]

简介

Catalyzes the oxygenation of arachidonate ((5Z,8Z,11Z,14Z)-eicosatetraenoate) to 5-hydroperoxyeicosatetraenoate (5-HPETE) followed by the dehydration to 5,6- epoxyeicosatetraenoate (Leukotriene A4/LTA4), the first two steps in the biosynthesis of leukotrienes, which are potent mediators of inflammation (PubMed:8631361, PubMed:21233389, PubMed:22516296, PubMed:24282679, PubMed:19022417, PubMed:23246375, PubMed:8615788, PubMed:24893149, PubMed:31664810). Also catalyzes the oxygenation of arachidonate into 8-hydroperoxyicosatetraenoate (8-HPETE) and 12-hydroperoxyicosatetraenoate (12-HPETE) (PubMed:23246375). Displays lipoxin synthase activity being able to convert (15S)-HETE into a conjugate tetraene (PubMed:31664810). Although arachidonate is the preferred substrate, this enzyme can also metabolize oxidized fatty acids derived from arachidonate such as (15S)-HETE, eicosapentaenoate (EPA) such as (18R)- and (18S)-HEPE or docosahexaenoate (DHA) which lead to the formation of specialized pro-resolving mediators (SPM) lipoxin and resolvins E and D respectively, therefore it participates in anti-inflammatory responses (PubMed:21206090, PubMed:31664810, PubMed:8615788, PubMed:17114001, PubMed:32404334). Oxidation of DHA directly inhibits endothelial cell proliferation and sprouting angiogenesis via peroxisome proliferator-activated receptor gamma (PPARgamma) (By similarity). It does not catalyze the oxygenation of linoleic acid and does not convert (5S)-HETE to lipoxin isomers (PubMed:31664810). In addition to inflammatory processes, it participates in dendritic cell migration, wound healing through an antioxidant mechanism based on heme oxygenase-1 (HO-1) regulation expression, monocyte adhesion to the endothelium via ITGAM expression on monocytes (By similarity). Moreover, it helps establish an adaptive humoral immunity by regulating primary resting B cells and follicular helper T cells and participates in the CD40-induced production of reactive oxygen species (ROS) after CD40 ligation in B cells through interaction with PIK3R1 that bridges ALOX5 with CD40 (PubMed:21200133). May also play a role in glucose homeostasis, regulation of insulin secretion and palmitic acid-induced insulin resistance via AMPK (By similarity). Can regulate bone mineralization and fat cell differentiation increases in induced pluripotent stem cells (By similarity).

关联

145

项与 5-LOX 相关的药物

Zileuton

齐留通

靶点

5-LOX

作用机制

5-LOX抑制剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期1996-12-09

Tipelukast

泰鲁司特

靶点

5-LOX x LTRs

作用机制

5-LOX抑制剂 [+1]

在研机构

KYORIN Pharmaceutical Co., Ltd. [+1]

原研机构

KYORIN Pharmaceutical Co., Ltd.

在研适应症

2型糖尿病 [+4]

非在研适应症

高胆固醇血症 [+1]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

MW-001

靶点

5-LOX x COX-2

作用机制

5-LOX抑制剂 [+1]

在研机构

Medwell Capital Corp.

原研机构

Medwell Capital Corp.

在研适应症

特应性皮炎 [+2]

非在研适应症

溃疡性结肠炎 [+3]

最高研发阶段临床2期

首次获批国家/地区-

首次获批日期1800-01-20

项与 5-LOX 相关的临床试验

NCT05464784 / Recruiting临床2期

A Phase 2, Double-Blind, Randomized, Placebo-Controlled Study to Evaluate the Safety, Tolerability and Efficacy of MN-001 in Patients Diagnosed With Non-alcoholic Fatty Liver Disease, Type 2 Diabetes Mellitus, and Hypertriglyceridemia

The design of the Phase 2 clinical trial includes the following elements:
Multi-center, two-arm, randomized, double-blind, placebo-controlled trial to evaluate MN-001 (tipelukast) vs. placebo in approximately 40 patients in the U.S.
Patients will be randomized 1:1 to receive either 500 mg/day of MN-001 (tipelukast) or placebo for 24 weeks.
The co-primary endpoints are (1) change from baseline in liver fat content measured by controlled attenuation parameter (CAP) score at Week 24, and (2) change from baseline in fasting serum triglycerides at Week 24. FebroScan is a non-invasive, quantitative, and accurate measure of liver fat content commonly used in early phase trials to measure treatment response.
Secondary endpoints include safety and tolerability and changes in lipid profile (HDL-C, LDL-C, and total cholesterol).

开始日期2022-08-22

申办/合作机构

MediciNova, Inc.

NCT03571620 / Completed临床2期

A Multicenter, Randomized, Phase 2, Double-blind, Vehicle-controlled, Parallel Group Comparison Study to Evaluate the Safety and Efficacy of Q301 Cream in Adolescents and Adults With Mild to Moderate Atopic Dermatitis

This is a randomized, double-blind, vehicle-controlled, parallel-group comparison study to evaluate the safety and efficacy of Q301 Cream vs. vehicle in adolescent and adult subjects with mild to moderate AD. Study drug (Q301 Cream or vehicle) will be administered topically twice a day for 8 consecutive weeks.

开始日期2018-06-21

申办/合作机构

Qurient Co., Ltd.

NCT02503657 / Completed临床2期

A Randomized, Placebo-Controlled, Double-Blind Six Month Study Followed by an Open-Label Extension Phase to Evaluate the Efficacy, Safety and Tolerability of MN-001 in Subjects With Idiopathic Pulmonary Fibrosis (IPF)

This is a randomized, placebo-controlled, double-blind, 6-month study followed by a 6 month open-label extension phase to evaluate the efficacy, safety, and tolerability of MN-001 in moderate to severe IPF patients. MN-001 750 mg or matching placebo will be orally administered twice daily over a 26 week period in subjects with a confirmed diagnosis of IPF per the ATS )American Thoracic Society) 2011 Guidelines. Approximately 15 subjects are planned to be enrolled. This study will consist of two treatment arms, MN-001 and matching placebo. Randomization will occur in a 2:1 ratio (MN-001: placebo). Eligible subjects will consist of males and females ranging in age from 21 to 80 years old, inclusive.
The study will consist of a Screening Phase (up to 3 months prior to Day1) followed by a 26 week double-blind Treatment Phase, a 26 week Open-Label Extension (OLE) phase and a Follow-up Visit (within 4 weeks after the last dose).

开始日期2016-03-09

申办/合作机构

MediciNova, Inc.

100 项与 5-LOX 相关的临床结果

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100 项与 5-LOX 相关的转化医学

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0 项与 5-LOX 相关的专利（医药）

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6,019

项与 5-LOX 相关的文献（医药）

2024-12-01·Journal of enzyme inhibition and medicinal chemistry

A multidisciplinary approach to the antioxidant and hepatoprotective activities of Arbutus pavarii Pampan fruit; in vitro and in Vivo biological evaluations, and in silico investigations.

Article

作者: Fatma A Elshibani ; Abdullah D Alamami ; Hamdoon A Mohammed ; Rabab Ahmed Rasheed ; Radwa M El Sabban ; Mohamed A Yehia ; Sherif S Abdel Mageed ; Taghreed A Majrashi ; Eslam B Elkaeed ; Mahmoud A El Hassab ; Wagdy M Eldehna ; Mohamed K El-Ashrey

The Libyan Strawberry, Arbutus pavarii Pampan (ARB), is an endemic Jebel Akhdar plant used for traditional medicine. This study presents the antioxidant and hepatoprotective properties of ARB fruit-extract. ARB phytochemical analysis indicated the presence of 354.54 GAE and 36.2 RE of the phenolics and flavonoids. LC-MS analysis identified 35 compounds belonging to phenolic acids, procyanidins, and flavonoid glycosides. Gallic acid, procyanidin dimer B3, β-type procyanidin trimer C, and quercetin-3-O-glucoside were the major constituents of the plant extract. ARB administration to paracetamol (PAR)-intoxicated rats reduced serum ALT, AST, bilirubin, hepatic tissue MDA and proinflammatory markers; TNF-α and IL-6 with an increase in tissue GSH level and SOD activity. Histological and immunohistochemical studies revealed that ARB restored the liver histology and significantly reduced the tissue expression of caspase 3, IL-1B, and NF-KB in PAR-induced liver damage. Docking analysis disclosed good binding affinities of some compounds with XO, COX-1, 5-LOX, and PI3K.

2024-12-01·Journal of enzyme inhibition and medicinal chemistry

Discovery of new thymol-3,4-disubstituted thiazole hybrids as dual COX-2/5-LOX inhibitors with in vivo proof.

Article

作者: Mostafa M M El-Miligy ; Ahmed K Al-Kubeisi ; Rasha A Nassra ; Saad R El-Zemity ; Aly A Hazzaa

New thymol-3,4-disubstitutedthiazole hybrids were synthesised as dual COX-2/5-LOX inhibitors. Compounds 6b, 6d, 6e, and 6f displayed in vitro inhibitory activity against COX-2 (IC₅₀= 0.037, 0.042, 0.046, and 0.039 µM) nearly equal to celecoxib (IC₅₀= 0.045 µM). 6b, 6d, and 6f showed SI (379, 341, and 374, respectively) higher than that of celecoxib (327). 6a-l elicited in vitro 5-LOX inhibitory activity higher than quercetin. 6a-f, 6i-l, 7a, and 7c possessed in vivo inhibition of formalin induced paw edoema higher than celecoxib. 6a, 6b, 6f, 6h-l, and 7b showed gastrointestinal safety profile as celecoxib and diclofenac sodium in the population of fasted rats. Induced fit docking and molecular dynamics simulation predicted good fitting of 6b and 6f without changing the packing and globularity of the apo protein. In conclusion, 6b and 6f achieved the target goal as multitarget inhibitors of inflammation.

2024-04-01·Oncology letters

Chemoprevention of esophageal adenocarcinoma in a rat surgical model by a cysteinyl leukotriene receptor‑1 antagonist.

Article

作者: Tatsuhiko Kohno ; Jun Kinoshita ; Katsunobu Oyama ; Hiroto Saito ; Mari Shimada ; Toshikatsu Tsuji ; Daisuke Yamamoto ; Hideki Moriyama ; Noriyuki Inaki ; Tetsuo Ohta

Reflux of gastroduodenal contents into the esophagus leads to the development of esophagitis and inflammation-associated pathologies, such as Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC). The role of the lipoxygenase (LOX) pathway in carcinogenesis has been recently reported; however, its involvement in esophageal carcinogenesis remains unclear. To address this, the present study investigated the potential of pranlukast, a cysteinyl leukotriene receptor-1 antagonist, to suppress the progression of BE and EAC in a rat duodenogastroesophageal reflux (DGER) model. Male Wistar rats that underwent DGER were divided into two groups. One group was fed commercial chow (control group), and the other was fed experimental chow containing pranlukast (pranlukast group). The rats were sacrificed at 10, 20, 30 and 40 weeks after surgery, and their esophagi were examined. Expression levels of 5-LOX, CD68, IL-8, VEGF and Ki-67 were investigated using immunohistochemistry, and apoptosis was analyzed using the TUNEL method. In the pranlukast group, esophagitis was milder, and the incidence of BE and EAC was significantly lower (P<0.05) compared with that in the control group at 40 weeks after surgery. The number of cells positive for IL-8 and VEGF were significantly lower in the pranlukast group compared with the control group. Proliferative activity was also lower in the pranlukast group compared with the control group (P<0.05). Pranlukast treatment increased apoptosis (P<0.05). Overall, Pranlukast suppressed esophageal carcinogenesis in a rat DGER model, decreasing inflammatory cytokines such as IL-8 and VEGF.

项与 5-LOX 相关的新闻（医药）

2024-03-20

·GlobeNewswire-Health Care

MediciNova Announces Two Abstracts regarding MN-001 (tipelukast) and MN-002 Accepted for Presentation at the 92nd EAS 2024 Congress, the Annual Meeting of the European Atherosclerosis Society

LA JOLLA, Calif., March 20, 2024 (GLOBE NEWSWIRE) -- MediciNova, Inc., a biopharmaceutical company traded on the NASDAQ Global Market (NASDAQ:MNOV) and the Standard Market of the Tokyo Stock Exchange (Code Number: 4875), today announced that two abstracts entitled “STUDY PROTOCOL TO EVALUATE MN-001’S (TIPELUKAST) EFFICACY, SAFETY AND TOLERABILITY IN SUBJECTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD), HYPERTRIGLYCERIDEMIA (HTG) AND TYPE-2 DIABETES MELLITUS (T2DM)” and “MN-002, THE METABOLITE OF MN-001(TIPELUKAST) PROMOTES MACROPHAGE CHOLESTEROL EFFLUX” have been accepted and selected for poster presentation at the 92nd European Atherosclerosis Society (EAS) 2024 Congress to be held May 26-29, 2024. MediciNova’s Chief Medical Officer, Kazuko Matsuda, MD PhD MPH will present the ongoing clinical trial design and objectives, and Dr. Qi Huicheng will present the results of the research to evaluate the mechanism of action of MN-001 (tipelukast) and MN-002 (a major metabolite of MN-001). Presentation details will be disseminated as they become available. Kazuko Matsuda, M.D. Ph.D., M.P.H., Chief Medical Officer, MediciNova, Inc., commented, “We are very pleased that the two presentations were accepted at the EAS 2024 Congress. One presentation is regarding the objectives and design of the ongoing Phase 2 clinical trial enrolling patients with Type 2 diabetes, dyslipidemia, and NAFLD. The other presentation is regarding the mechanism of action of MN-001/MN-002 in lipid metabolism, particularly the effects on cholesterol efflux capacity. This is the outcome from our research collaboration with Professor Takashi Mitsui MD PhD, and Professor Masatsune Ogura MD PhD at Juntendo University to evaluate the mechanism of action of MN-001 in lipid metabolism and metabolic syndrome”. About NAFLD, Type 2 Diabetes Mellitus, and Hypertriglyceridemia NAFLD is considered the hepatic manifestation of metabolic syndrome; studies have reported that 50% of patients with metabolic syndrome also have NAFLD. There is sufficient clinical and epidemiological evidence supporting the assertion that NAFLD is strongly associated with an increased prevalence and incidence of cardiovascular disease, T2DM, chronic kidney disease, and malignancy. The presence of dyslipidemia (hypercholesterolemia, hypertriglyceridemia, or both) is reported in 20 - 80% of NAFLD cases. About MN-001 MN-001 (tipelukast) is a novel, orally bioavailable, small molecule compound thought to exert its effects through several mechanisms to produce its anti-inflammatory and anti-fibrotic activity in preclinical models, including leukotriene (LT) receptor antagonism, inhibition of phosphodiesterases (PDE) (mainly 3 and 4), and inhibition of 5-lipoxygenase (5-LO). The 5-LO/LT pathway has been postulated as a pathogenic factor in fibrosis development, and MN-001's inhibitory effect on 5-LO and the 5-LO/LT pathway is a novel approach to treat fibrosis. MN-001 has been shown to down-regulate expression of genes that promote fibrosis including LOXL2, Collagen Type 1 and TIMP-1. MN-001 has also been shown to down-regulate expression of genes that promote inflammation including CCR2 and MCP-1. In addition, MN-001 was found to inhibit triglyceride synthesis in hepatocytes by inhibiting arachidonic acid uptake. About MediciNova MediciNova, Inc. is a clinical-stage biopharmaceutical company developing a broad late-stage pipeline of novel small molecule therapies for inflammatory, fibrotic, and neurodegenerative diseases. Based on two compounds, MN-166 (ibudilast) and MN-001 (tipelukast), with multiple mechanisms of action and strong safety profiles, MediciNova has 11 programs in clinical development. MediciNova’s lead asset, MN-166 (ibudilast), is currently in Phase 3 for amyotrophic lateral sclerosis (ALS) and degenerative cervical myelopathy (DCM) and is Phase 3-ready for progressive multiple sclerosis (MS). MN-166 (ibudilast) is also being evaluated in Phase 2 trials in glioblastoma, Long COVID, and substance dependence. MN-001 (tipelukast) was evaluated in a Phase 2 trial in idiopathic pulmonary fibrosis (IPF) and a second Phase 2 trial in non-alcoholic fatty liver disease (NAFLD) is ongoing. MediciNova has a strong track record of securing investigator-sponsored clinical trials funded through government grants. Statements in this press release that are not historical in nature constitute forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. These forward-looking statements include, without limitation, statements regarding the future development and efficacy of MN-166, MN-001, MN-221, and MN-029. These forward-looking statements may be preceded by, followed by, or otherwise include the words "believes," "expects," "anticipates," "intends," "estimates," "projects," "can," "could," "may," "will," "would," “considering,” “planning” or similar expressions. These forward-looking statements involve a number of risks and uncertainties that may cause actual results or events to differ materially from those expressed or implied by such forward-looking statements. Factors that may cause actual results or events to differ materially from those expressed or implied by these forward-looking statements include, but are not limited to, risks of obtaining future partner or grant funding for development of MN-166, MN-001, MN-221, and MN-029 and risks of raising sufficient capital when needed to fund MediciNova's operations and contribution to clinical development, risks and uncertainties inherent in clinical trials, including the potential cost, expected timing and risks associated with clinical trials designed to meet FDA guidance and the viability of further development considering these factors, product development and commercialization risks, the uncertainty of whether the results of clinical trials will be predictive of results in later stages of product development, the risk of delays or failure to obtain or maintain regulatory approval, risks associated with the reliance on third parties to sponsor and fund clinical trials, risks regarding intellectual property rights in product candidates and the ability to defend and enforce such intellectual property rights, the risk of failure of the third parties upon whom MediciNova relies to conduct its clinical trials and manufacture its product candidates to perform as expected, the risk of increased cost and delays due to delays in the commencement, enrollment, completion or analysis of clinical trials or significant issues regarding the adequacy of clinical trial designs or the execution of clinical trials, and the timing of expected filings with the regulatory authorities, MediciNova's collaborations with third parties, the availability of funds to complete product development plans and MediciNova's ability to obtain third party funding for programs and raise sufficient capital when needed, and the other risks and uncertainties described in MediciNova's filings with the Securities and Exchange Commission, including its annual report on Form 10-K for the year ended December 31, 2023 and its subsequent periodic reports on Form 10-Q and current reports on Form 8-K. Undue reliance should not be placed on these forward-looking statements, which speak only as of the date hereof. MediciNova disclaims any intent or obligation to revise or update these forward-looking statements. INVESTOR CONTACT:Geoff O'BrienVice PresidentMediciNova, Inc.info@medicinova.com

临床2期临床3期

2024-03-03

·动脉网

D轮融资1.7亿美元，礼来、安进加持，这家公司用AI解决衰老问题

2024年才走过近两个月的时间，抗衰领域已诞生一笔1.7亿美元的融资。获得融资的企业名为BioAge Labs（下文简称BioAge），是一家成立于2015年的抗衰明星公司，致力于利用AI技术开发治疗衰老和年龄相关性疾病、延长人类健康寿命的创新药物。而在该公司宣布完成D轮融资后不久，其还于近日宣布将于2024年中期启动与礼来合作的一项2期临床试验，以评估BioAge的Apelin受体（APJ）激动剂Azelaprag（BGE-105）与礼来的GLP-1R/GIPR双靶点激动剂 Tirzepatide（替尔泊肽）的联合疗法在治疗肥胖症中的疗效。并且，动脉网了解到，在试验过程中，BioAge也将在遵守相关法律法规的基础上收集受试者的衰老相关生物标志物信息，以此助力BioAge其他处于临床早期衰老管线的研发。截至目前，BioAge针对衰老问题的研究集中在3个方向，分别是代谢和肌肉衰老、大脑衰老、免疫衰老。同时，依托独有的AI药物发现平台，BioAge还拥有多条在研管线，适应症包括肥胖症、神经炎症、急性肌肉萎缩等与衰老相关的疾病。明星团队支撑，获近3亿美元融资成立至今，BioAge已完成5轮融资，共募资近3亿美元，Andreessen Horowitz、Pear Ventures以及AME Cloud Ventures等投资者更是多轮押注，并且先后与安进和礼来达成合作。BioAge融资过程数据来源：crunchbase官网，动脉网制图BioAge备受明星资本青睐和知名企业看重的背后，是一支从默克、罗氏、英矽智能等企业的核心团队作支撑。其联合创始人兼首席执行官Kristen Fortney博士是一位在生物信息学领域拥有超10年研究经验的创业者。她不仅获得了多伦多大学生物信息学博士学位并在斯坦福大学接受博士后培训，还成为了两个知名衰老研究机构——American Federation for Aging Research（美国老龄化研究联合会）和Ellison Medical Foundation（埃里森医学基金会）的研究员，发表论文共计18篇，研究领域包括计算药物发现、衰老生物标志物和延长人类寿命的遗传学等。此外，Kristen Fortney曾担任Insilico Medicine、Humanity、Retro Biosciences、Known Medicine等药物研发公司的顾问。值得一提的是，BioAge识别和靶向驱动衰老的分子途径的数据驱动方法正是由其主导开发。并且，与创始人相似的是，BioAge的核心团队成员也具有衰老研究和系统生物学的深厚背景——其首席运营官Eric Morgen在靶点发现、衰老、药物基因组学等领域发表了20余篇论文；担任公司首席营销官兼执行副总裁一职的Paul Rubin博士曾在MiRagen、Glaxo-Wellcome、Abbott等生物制药公司担任要职，并将10多种产品从临床开发推动至获批，其中包括第一个获批用于临床治疗哮喘的5-脂氧合酶抑制剂齐留通（Zileuton）。同时，BioAge还吸引了Peng Leong博士出任首席商务官兼脑衰老治疗领域负责人一职，Peng Leong博士此前曾在CIBC World Markets和Piper Jaffray从事医疗投资银行业务，并曾担任默克的医学业务开发主管以及Kazia Therapeutics的首席品牌官。此外，BioAge的科学顾问团队也为公司的发展保驾护航，主要成员包括抗血小板药物Aggrastat®的主要研发人George Hartman博士，曾负责罗氏抗病毒药物临床开发的Klaus Klumpp博士，以及曾在Twitter、Google、麦肯锡公司担任企业战略副总裁、产品经理的Elad Gil博士等，他们的加入为公司的核心管线推进提供了研发动力。独有AI平台：基于6550万+数据点，每年评估约20种衰老途径2019年，BioAge宣布完成2300万美元B轮融资，该轮资金推动了公司搭建基于AI技术的高通量目标识别平台，即AI药物发现平台。该平台能够在海量的数据中搜索并确定影响人类寿命的关键生物途径和药物靶点，并通过高通量生物验证、最终将潜在靶点推进临床开发阶段。但BioAge并不止步于简单的检索验证，公司期望通过集成更多的AI技术和数据库信息，将原有平台升级为一个由AI驱动，可利用大量生物数据来发现、验证更广泛的衰老途径和药物靶点的技术平台。为此，在2022年BioAge宣布与Age Labs达成合作协议，获得了对AgeLabs数据库的独家访问权，BioAge能够使用Nord-Trøndelag健康研究（HUNT）生物库样本和健康记录来识别、开发和商业化针对衰老疾病的药物靶点。值得关注的是，HUNT自1995年至今纵向收集的生物样本适用于表观遗传学、蛋白质组学和代谢组学分析。在此基础上，BioAge的AI药物发现平台可深入分析来自纵向的生物样本，识别影响健康长寿和与年龄相关性疾病的蛋白质、代谢物或分子机制，而后快速确定衰老途径中的关键靶点。经过多年创新发展，BioAge的平台目前建立在一个拥有45年长度的纵向样本和健康记录的数据库上，拥有150万多个临床数据点、6400万多个分子数据点共6550万多个数据点，每年可评估约20种衰老途径。其中，该平台的最大优势是根据纵向数据跟踪患者衰老结果，从而确定导致衰老发生的新机制和驱动因素，并在已知和新型衰老生物学的交叉点上识别全新靶点。临床前试验显示小鼠体重减轻2倍，BioAge拳头产品可实现减脂不减肌Azelaprag正是BioAge通过AI平台发现并推进研发的在研管线。2021年，BioAge与安进签订了一项全球独家许可协议，获得了该药物的开发和商业化的权利。经过2年多研发推进，Azelaprag已成为公司目前在代谢和肌肉衰老领域的重要资产Azelaprag是一款可口服或静脉注射的APJ激动剂，可用于治疗肌肉萎缩并通过提高Apelin信号活性来恢复肌肉力量和功能。其中，Apelin是一种在运动后释放的“运动因子”多肽，其内生受体APJ是一种G蛋白偶联受体，在体内多种器官细胞上表达，主要包括中枢神经系统跟心血管系统，并通过与骨骼肌、心脏和中枢神经系统的相互作用调节新陈代谢，促进肌肉再生。研究显示，当人体开始衰老时，其骨骼和肌肉质量会逐渐减少，骨折、虚弱等风险也相应增加，比如，多发于老年人群体的肌肉萎缩，对于他们来说，肌肉衰老会导致力量、活动能力和功能丧失，进而导致与年龄相关的疾病和死亡发生率的增加。数据显示，功能性肌肉减少症或与年龄相关的肌肉骨骼变化影响7%的70岁以上的老年人1。BioAge的研究也证明，人体的总体Apelin水平会随着衰老过程而逐渐下降，而Apelin水平较高的人具有更强的身体功能和更长的寿命。其临床前研究显示，Azelaprag与替尔泊肽联合使用可增加受试小鼠整体体重减轻效果，与单独使用替尔泊肽相比，Azelaprag组的受试小鼠体重减轻了2倍，并且能够将身体成分和肌肉功能恢复到可控水平。在Azelaprag的1b期临床试验中，数据显示，21名65岁及以上的健康受试者在接受Azelaprag或安慰剂输注并严格卧床休息10天后，与安慰剂相比，Azelaprag在肌肉大小、质量和蛋白质合成方面产生了统计学上的显著改善，且并未产生严重副作用，具有良好的安全性和耐受性。基于积极的临床试验数据，BioAge将与礼来合作开展一项2期临床试验，评估Azelaprag是否可以增强GLP-1药物所实现的减肥效果。作为一款防止肌肉衰老的药物，Azelaprag与GLP-1药物联合用药，将有可能减轻该类药物引起的胃肠道问题和肌肉质量损失等副作用，促进实现更健康的减肥效果，最终通过治疗肥胖有效预防或延缓多种衰老疾病进展、延长患者的健康寿命。布局多条在研管线，探索抗衰无限可能性在AI平台的支持下，BioAge针对衰老领域中的不同适应症布局了多条在研管线，除了前文提到的核心管线Azelaprag外，还包括BGE-100。BioAge在研管线图源：BioAge官网BGE-100是一种NLRP3（NOD样受体热蛋白结构域相关蛋白3）抑制剂，被开发用于治疗由神经炎症引起的神经退行性疾病，帮助延长患者寿命。目前，BGE-100处于临床前毒理学研究阶段，预计将于2024年年中进入临床试验。值得关注的是，BioAge还曾布局了其他两款衰老管线——BGE-175和BGE-117。其中，BGE-175是一种前列腺素D2（PGD2）DP1 受体的抑制剂，被开发用于治疗因免疫老化导致的多种疾病，实现修复老化的免疫系统的目的。BGE-117是一种缺氧诱导因子-脯氨酰羟化酶（HIF-PH）抑制剂，被开发用于治疗多种衰老疾病，从而提高老年人寿命。不过，BioAge先后在2021年放弃了BGE-175和BGE-117两项资产，将重点转至BGE-100和Azelaprag，并逐步将赛道从衰老覆盖至减肥领域。对此，Kristen Fortney表示，对代谢疾病领域的关注将同时促进公司衰老领域的业务发展，最终将促进解决衰老以及与年龄相关疾病治疗的问题。尽管创新药物研发这条路还很长，但是在未来，BioAge的在研药物也许会成为患者摆脱疾病困扰、延长健康寿命的希望。参考资料：1. Amarya S, Singh K, Sabharwal M. Ageing process and physiological changes[M]//Gerontology. IntechOpen, 2018.文|冯汝梅微信|echo822207添加时请注明：姓名-公司-职位网站、公众号等转载请联系授权：Rekkiiie近期推荐声明：动脉网所刊载内容之知识产权为动脉网及相关权利人专属所有或持有。未经许可，禁止进行转载、摘编、复制及建立镜像等任何使用。动脉网，未来医疗服务平台

临床2期高管变更

2023-12-06

·CPHI制药在线

天然产物治疗特应性皮炎的药理研究进展

关注并星标CPHI制药在线特应性皮炎（atopic dermatitis，AD）是一种T细胞诱导的异质性很强的慢性炎症性皮肤病，临床表现为红斑、丘疹、苔藓样改变、剧烈瘙痒等。特应性皮炎的发病原因与发病机制尚不完全清楚，近年来大多认为遗传、代谢障碍，感染、免疫功能障碍等可能为发病的重要因素，季节变化、潮湿、精神创伤或手术等也可能诱发。遗传因素是AD致病的最强风险因素，研究显示，父母患 AD 的子女发病率较高。与其相关致病基因主要有皮肤屏障、固有免疫反应及特异性免疫反应。AD 涉及的主要免疫反应为Th1/Th2 平衡失调引起细胞因子的分泌异常。在AD急性期，以 Th2型占优势，活化的Th2 细胞通过释放白介素IL-4、IL-5、IL-6、IL-9、IL-10和IL-13等细胞因子诱导B细胞产生免疫球蛋白E（IgE），使IgE水平增高；产生的 IL-5 细胞因子延长嗜酸粒细胞生存时间，引起系统嗜酸性粒细胞的升高，加重皮肤局部炎症反应。在AD慢性期以 Th1 型占优势，Th1细胞产生干扰素γ（IFN-γ）、TNF-β、IL-2、IL-12、IL-18 等细胞因子参与细胞介导的炎症反应。环境因素包括空气污染、被动吸烟、环境变应原如屋尘螨、花粉等，都会增加AD 的患病率。环境中的抗原通过受损的皮肤屏障刺激抗原呈递细胞，使局部淋巴结中的 Th2 细胞与T细胞/B细胞相互作用，导致IgE过度的转换；同时记忆T细胞重新分布到血液循环中，通过T细胞皮肤浸润使AD恶化，并扩散到皮肤以外导致其他特应性疾病发生。AD 患者常有皮肤屏障功能的缺陷，其发病机制主要表现在表皮蛋白质分泌异常、表皮脂质表达谱异常、水通道蛋白（AQPs）表达异常、表皮细胞紧密连接（TJ）功能受损和抗菌肽（AMPs）的表达失调等方面。此外精神紧张、焦虑、抑郁等方面是也是 AD 患者疾病恶化的重要原因。天然产物是新药研发的重要来源，得益于丰富的中药研究基础，我国对天然产物的开发与利用有着天然的优势。众多基础研究显示，天然产物具有较高的安全性和有效性，可通过抑制NF-κB相关信号通路，显著改善AD的过敏性炎症和氧化应激状态。 01黄酮类黄芩黄酮II（SFII）是从黄芩中分离出来的类黄酮，具有抗炎、抗菌、抗氧化作用。体外实验研究发现SFII 可通过调节信号传导与转录激活因子（STAT）1、NF-κB和p38 MAPK信号通路来抑制胸腺活化调节趋化因子（TARC/CCL17）和巨噬细胞来源的趋化因子（MDC/CCL22）和CTSS等趋化因子和炎症介质的表达。黄芩苷是另一种从黄芩中提取的活性化合物。研究发现黄芩苷可通过调节Th1/Th2 平衡，上调丝聚蛋白（FLG）、内披蛋白（IVL）、兜甲蛋白（LOR）等屏障蛋白表达以改善皮肤屏障功能，恢复AD小鼠肠道益生菌丰度以调节肠道生态失调，并通过抑制 NF-κB和Janus激酶（JAK）/STAT 通路的活化来抑制AD样炎症。槲皮素是类黄酮化合物的糖基化形式，存在于大多数可食用的水果和蔬菜中，具有有效的抗氧化和抗炎特性。研究发现，口服槲皮素不仅可减轻粉尘螨提取物（DFE）诱导的NC/Nga小鼠AD样皮损的发展和组织病理学改变，还可下调细胞质 HMGB1、RAGE 以及细胞核中p-NF-κB、p-ERK1/2、COX-2、TNF-α、IL-1β、IL-2Rα、IFN-γ 和IL-4等炎症因子水平，同时上调细胞核 Nrf2水平。表明槲皮素可通过调节 HMGB1/RAGE/NF-κB 信号传导和 Nrf2 蛋白的诱导，有望成为AD 的治疗药物。白杨素是一种来源于蜂胶、蔬菜和水果的天然类黄酮，对肥大细胞介导的过敏反应具有抑制作用。研究发现，口服白杨素可减轻二硝基氯苯（DNCB）/DFE诱导的AD样症状以及血清 IgE、IgG2a和组胺水平，还可抑制小鼠淋巴结和耳组织中Th1/Th2/Th17/Th22 的相关炎症反应。体外实验表明，白杨素可通过下调p38 MAPK、NF-κB和STAT1的活化降低 TNF-α、IL-1β、IL-6 等促炎细胞因子及 CCL17、CCL22 等 Th2 趋化因子，还可通过下调 TNF-α/IFN-γ刺激的 HaCaT 细胞和小鼠原代角质形成细胞中 IL-33 表达来抑制先天免疫系统。桑皮酮G和桑辛素是从桑树中提取的黄酮类化合物。体外研究显示桑皮酮G可通过下调 TNF-α/IFN-γ 刺激的 HaCaT 细胞中的STAT1 和 NF-κB p65 信号传导，减少了趋化因子配体5（RANTES/CCL5）、TARC 和 MDC 的释放，还可抑制佛波酯（PMA）/钙霉素（A23187）刺激的MC/9 肥大细胞中的组胺产生和5-脂氧合酶（5-LO）的活化。桑辛素可通过抑制TNF-α/IFN-γ刺激的HaCaT 细胞中的STAT1和NF-κB p65 磷酸化来抑制RANTES 和TARC 的分泌，并抑制PMA/A23187 刺激的 MC/9 肥大细胞中的组胺产生和5-LO活化释放的LTC4。白三烯（LT）是由花生四烯酸在5-LO、LTA4水解酶和 LTC4合酶的作用下合成的脂质介质，在炎症反应中起重要作用。可见桑皮酮 G 和桑辛素具有治疗过敏性和炎症性皮肤病的潜力。 02生物碱甲基莲心碱是从莲花成熟种子的绿色胚胎中分离出来的小分子化合物。研究发现甲基莲心碱可抑制细胞因子（IL-1β、IL-6、IL-8、TSLP）、趋化因子（TARC、MDC、RANTES）的表达以及NF-κB和MAPK的磷酸化。此外，还可显著减轻小鼠模型的皮肤屏障损伤、经表皮失水、抓挠反应和表皮增生，并增加表面皮肤水合作用。伪麻黄碱（PSE）是一种来自麻黄属麻黄草和中麻黄的生物碱，因其血管收缩作用已批准作为拟交感神经药物减轻普通感冒期间的鼻塞。研究发现，口服 PSE可改善DNCB诱导的AD 样皮炎、皮肤水合作用及抓挠行为，抑制血清TNF-α和IgE 水平，降低皮肤组织中众多细胞因子和趋化因子如CCL2、基质金属蛋白酶（MMP）-9 的表达，抑制了TNF-α/IFN-γ 诱导的 HaCaT 细胞中炎症因子TNF-α，IL-1β 和IL-23 的释放。此外，PSE 在体内和体外均可抑制MAPK和NF-κB 信号通路的激活。 03酚类姜黄素和双去甲氧基姜黄素（BDMC）是来自中药姜黄根茎的成分。研究证实，姜黄素对皮肤炎症、增殖和感染性疾病有调节作用。BDMC比姜黄素更稳定且具有更好的水溶性和渗透性，能够抑制趋化因子和炎性细胞因子的 mRNA 表达以及MAPK和NF-κB信号通路的激活，缓解AD炎症反应。白藜芦醇是一种多酚，大量存在于红葡萄皮中，可有效抗炎和对抗衰老。研究发现，白藜芦醇对HMGB1-RAGE、PI3K、ERK1/2和NF-κB 通路具有抑制作用，可能是抗炎治疗的有效靶点。另有研究显示，白藜芦醇可改善细胞浸润，抑制皮肤肥大细胞激活和趋化因子表达，降低产生一磷酸鞘氨醇（S1P）的鞘氨醇激酶 1（SphK1）的活化，以及参与趋化因子产生的STAT3 和 NF-κB p65 的活化，而生物活性鞘脂代谢物 S1P 激活肥大细胞会引发大量皮肤重塑。 04萜类菊科植物土木香以其抗炎作用而闻名，广泛用于化妆品和药品。从土木香中分离的 Igalan是一种倍半萜内酯。体外研究证实，Igalan可抑制NF-κB和STAT途径的活化下调TARC、MDC、RANTES 等炎症介质，还可通过抑制JAK/STAT3信号传导来上调 FLG、LOR、角蛋白10（KRT10）和桥粒糖蛋白1（DSC1）的mRNA 水平来促进皮肤屏障功能，并通过诱导Nrf2 通路及HO-1或 NAD(P)H 醌脱氢酶1（NQO1）等子序列基因调控细胞的抗氧化反应。此外，Igalan 还可抑制合成 NO 的 iNOS 的表达，有助于预防AD 中活性氧的风险。刺囊酸（ECA）是一种皂角的果实中提取的五环三萜，有很强的抗炎、抗氧化、抗肿瘤活性。ECA可通过恢复丝聚蛋白表达和皮肤水合作用来改善皮肤屏障功能，还可抑制尘螨诱导AD小鼠皮肤和肺T辅助细胞来源细胞因子的表达、ERK 和 STAT1 的磷酸化、角质形成细胞中 NF-κB 的易位，具有作为抗特应性和抗过敏的治疗潜力，阻止特应性进程的发展。齐墩果酸（OA）是一种五环三萜类化合物，大量存在于油橄榄科植物中。研究显示，OA对肥大细胞介导的过敏性炎症有抑制作用。OA 可通过阻断 Akt、NF-κB以及 STAT1抑制Th2 型细胞因子和趋化因子的表达。积雪草酸是在积雪草、猕猴桃、番石榴等多种植物中发现的一种五环三萜类化合物，研究发现积雪草酸可下调Th1/Th2 相关细胞因子以及 COX-2、C-X-C 基序趋化因子配体（CXCL）9、CXCL8的表达。同时，NF-κB、p-Akt、MAPK信号通路的活性也受到抑制。香紫苏醇属于天然二萜烯，是从紫苏的叶子和花中提取的化合物。研究发现，腹腔注射香紫苏醇除了显著减轻AD小鼠模型症状、血清IgE水平、局部皮损促炎细胞因子浓度，还可抑制T 细胞活化。 05香豆素类补骨脂呋喃香豆精是一种来自补骨脂果实的呋喃香豆素化合物，具有抗炎和抗感染作用。研究发现，胃内给予补骨脂呋喃香豆精可减轻 DNCB/DFE诱导的AD样皮肤炎症，抑制耳组织中IL-4、IL-13、IL-31、CCL17等Th2 相关细胞因子和趋化因子的表达，并降低小鼠血清中总IgE、DFE特异性IgE、IgG2a 的水平。体外实验表明，补骨脂呋喃香豆精不仅可抑制炎症介质的表达，还可抑制STAT1 磷酸化，IκBα降解和NF-κB 核易位。伞形花内酯（UMB）是一种香豆素衍生物，存在于紫花前胡、茵陈蒿等植物的根和树皮中，具有抗炎、抗糖尿病、抗癌、护肝作用。研究显示，口服UMB 可显著降低DNCB/DFE 诱导的AD小鼠IgE、IgG1、IgG2a、TNF-α和IL-4 的血清水平。此外，UMB可通过调节MAPK、NF-κB 和STAT1 信号通路，减少TNF-α/IFN-γ 刺激产生的促炎细胞因子和趋化因子的分泌，从而改善 AD 相关症状和炎症。秦皮乙素是从水曲柳的树皮中提取的香豆素类化合物。在哮喘动物模型中显示出抗炎作用，调节气道平滑肌细胞的表型切换。研究表明，口服秦皮乙素还可改善DFE/DNCB 诱导的AD样症状和组织学改变，降低血清中的IgE、IgG2a和组胺水平，抑制组织中Th1/Th2/Th17相关细胞因子的产生。体外实验也证实其能够抑制TNF-α/IFN-γ刺激的NF-κB和STAT1活化。 06其他五味子脂素 M2（GM2）是一种从五味子分离得到的木脂素，具有抗炎、抗过敏、抗病毒和抗癌作用。研究发现，GM2 可通过抑制STAT1 磷酸化和NF-κB的核易位而显著抑制IL-1β、IL-6、CXCL8和CCL22等炎症介质的水平。大黄素甲醚是从中药大黄中得到的蒽醌类物质，具有抗炎、抗微生物、抗肿瘤多种药理特性。体内外实验研究表明，大黄素甲醚可以通过Caspase-1/MAPK/NF-κB信号抑制TSLP 水平来改善AD样皮肤病变。西红花苷又称藏红花素，是一类水溶性类胡萝卜素，外用西红花苷可阻断DFE诱导的AD小鼠中的NF-κB 和STAT6 信号通路来抑制Th2相关细胞因子和趋化因子的表达。参考资料 [1]芶莉,刘冰梅,魏艳楠.中西医治疗特应性皮炎的研究进展[J].中文科技期刊数据库(文摘版)医药卫生,2023,(第11期). [2]李想,董玲玲,郭涛等.基于NF-κB信号通路天然产物治疗特应性皮炎的研究进展[J/OL].中国实验方剂学杂志,1-10 作者简介：小米虫，药品质量研究工作者，长期致力于药品质量研究及药品分析方法验证工作，现就职于国内某大型药物研发公司，从事药品检验分析及分析方法验证。智药研习会12月线上课程报名来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com▼更多制药资讯，请关注CPHI制药在线▼点击阅读原文，进入智药研习社~

细胞疗法