A 4-Week, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study to Investigate the Safety and Efficacy of EVT 101 as Monotherapy in Patients With Treatment-Resistant Major Depression

This study is a 4-week, randomized, double-blind, parallel-group, placebo-controlled monotherapy study in patients with treatment-resistant major depression. After confirmation of treatment-resistance in a prospective treatment period with citalopram, each patient will be treated with either EVT 101 once daily or placebo for 28 consecutive days.

开始日期2010-06-01

申办/合作机构

Janssen Research & Development LLC

[+1]

NCT00526968 / Completed临床1期

A Double Blind, Placebo Controlled Study to Investigate the Role of NMDA Receptor NR2B Subunit Selective Antagonism on Cognitive Functions and Neurophysiology in Healthy Subjects as Measured With MRI

The purpose of this study is to investigate the neurophysiological changes following single doses of EVT 101 using fMRI during rest and during cognitive tasks in young healthy male subjects.

开始日期2007-09-01

申办/合作机构

Evotec International GmbH

[+1]

100 项与 EVT-101 相关的临床结果

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100 项与 EVT-101 相关的转化医学

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100 项与 EVT-101 相关的专利（医药）

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项与 EVT-101 相关的文献（医药）

2023-05-01·European Journal of Medicinal Chemistry

Discovery of novel tryptamine derivatives as GluN2B subunit-containing NMDA receptor antagonists via pharmacophore-merging strategy with orally available therapeutic effect of cerebral ischemia

Article

作者: Cheng, Maosheng ; Yang, Huali ; Zhao, Ying ; Qin, Fengyun ; He, Yeli ; Quan, Jishun ; Ma, Chao ; Liu, Jiao

A series of tryptamine derivatives has been designed and synthesized as novel GluN2B subunit-containing NMDA receptor (GluN2B-NMDAR) antagonists, which could simultaneously manifest the receptor-ligand interactions of representative GluN2B-NMDAR antagonists ifenprodil (1) and EVT-101 (3). In the present study, the neuroprotective potential of these compounds was explored through chemical synthesis and pharmacological characterization. Compound Z25 with significantly better neuroprotective activity than the positive control drug (percentage of protection: 55.8 ± 0.6% vs. 41.0 ± 2.7%) was considered to be an effective antagonist of the human GluN2B-NMDA receptor. Judging from in vitro pharmacological profiling, Z25 could downregulate NMDA-induced increased intracellular Ca²⁺ concentration, and Z25 could also upregulate NMDA-induced decreased intracellular p-ERK 1/2 expression, which suggested that Z25 is an antagonist of the GluN2B-NMDA receptor. Furthermore, the in vitro preliminary evaluation of the drug-like properties of compound Z25 showed remarkable plasma stability. Based on in vivo pharmacokinetic and pharmacodynamic studies in C57 mice, compound Z25 exhibited a relatively short half-life and a low F value (3.12 ± 0.01%), while administration of Z25 substantially improved the cognitive performance of mice in a series of tests of cerebral ischemic injury. Overall, these results support the further development of compound Z25 as a potential lead compound to treat the cerebral ischemic injury by antagonizing GluN2B-NMDA receptor.

2021-07-24·Journal of Biomolecular Structure and Dynamics

Repurposing of cefpodoxime proxetil as potent neuroprotective agent through computational prediction and in vitro validation

Article

作者: Cheng, Maosheng ; Hu, Baichun ; Wang, Jian ; Zhang, Zhuo ; Ma, Chao ; Wang, Ying ; Zhang, Dongping ; Quan, Jishun

In recent reports, NR2B-NMDA receptor antagonists showed more research value because of its strong targeting ability and less side effects potential. In 2016, EVT-101 was reported to bind in an almost entirely new binding region of this target. Whether strikingly different binding modes can improve targeting and reduce side effects is worth studying. In our preliminary work, we explored the binding patterns of ifenprodil and EVT-101, found the key amino acids and summarized the pharmacophores, hoping to find such antagonists that target the two binding modes simultaneously. In this study, we developed a scalable virtual screening workflow in the FDA-approved drugs library to identify novel NR2B-NMDAR antagonists based on the combination of two pharmacophores. Cefpodoxime proxetil (5) was identified as the hit compound, and it was found for the first time that 5 might have neuroprotective activity as a NR2B-NMDAR antagonist. This result interested us to make further study, the ligand-receptor interactions modeled by molecular docking studies showed that the compound could perfectly merge both the pharmacophore characteristics of ifenprodil and EVT-101 at the binding cavity between the ATDs of GluN1 and GluN2B. The accuracy of molecular docking results and binding stability of ligand-receptor complexes were validated through 100 ns molecular dynamics simulation and binding free energy calculation. Afterwards, MTT assay (49.8%±0.1%, 5 μM) on NMDA injured SH-SY5Y cells and evidence of the effect on attenuating Ca²⁺ influx induced by NMDA were applied to validate the computational results, further investigation showed that 5 could suppress the NR2B upregulation induced by NMDA. [Formula: see text] Communicated by Ramaswamy H. Sarma.

2021-05-19·ACS Chemical Neuroscience3区 · 医学

Inhibition of the ERK1/2 Phosphorylation by Dextromethorphan Protects against Core Autistic Symptoms in VPA Induced Autistic Rats: In Silico and in Vivo Drug Repurposition Study

3区 · 医学

Article

作者: Sharma, Amit Raj ; Medhi, Bikash ; Singla, Rubal ; Mishra, Abhishek ; Kaur, Gurjeet ; Kumar, Rohit ; Sarma, Phulen ; Joshi, Rupa ; Bhatia, Alka

The imbalance between excitatory and inhibitory neurotransmitters is explicitly related to the pathophysiology of autism spectrum disorder (ASD). The role of an NMDA receptor antagonist, dextromethorphan, was studied in ameliorating the ASD-like symptoms by regulating the excitatory and inhibitory imbalance using the valproic acid (VPA) model of ASD. Female Wistar rats were administered VPA [600 mg/kg on embryonic day ED-12.5] through intraperitoneal (ip) injection to induce ASD in pups. Autistic pups were then given dextromethorphan (10, 15, and 30 mg/kg; ip) and risperidone (2.5 mg/kg; ip) from PND 23 to 43 in different groups. Behavioral tests (three chamber sociability, self-grooming, Morris water maze, elevated plus maze, open field, rotarod, grip strength), oxidative stress and inflammatory markers, histological evaluation (H&E, Nissil staining), and NMDA and ERK1/2 expression by immunohistochemistry and RT-PCR were done. The in silico modeling of dextromethorphan against PPDA, TCN-201, MK-22, EVT-101 on NMDA receptors was also performed. Dextromethorphan (30 mg/kg) rescued the impaired behavioral patterns including social excitability, hyperactivity, repetitive and restricted behaviors as well as mitigation of the memory and motor coordination. The levels of various oxidative stress markers (GSH, SOD, catalase, MDA) and inflammatory markers (IL-1β, IL-6, IL-10, TNF-α) were ameliorated by different doses of dextromethorphan. It also reduced the neuronal injury score and rescued the overly expressed pERK1/2 and NMDA signaling in both the prefrontal cortex and hippocampus of the autistic pups. In silico results showed favorable binding of dextromethorphan against TCN-201 and MK-22 binding sites. The present study provided experimental evidence for the potential therapeutic role of dextromethorphan in attenuating autism symptomatology in the ASD model of rats. Thus, modulation of the glutamatergic signaling can be a potential target for ASD treatment.

项与 EVT-101 相关的新闻（医药）

2023-05-19

·PRNewswire

Endsulin Announces Passing of Founder Hans Sollinger, MD, PhD

The award-winning transplant surgeon and world leader in diabetes research revolutionized the field of transplantation through the development of a novel kidney pancreas transplant technique that significantly improved patient outcomes MADISON, Wis., May 19, 2023 /PRNewswire/ -- Endsulin announced today that Founder and Chief Scientific Officer Hans Sollinger, M.D., Ph.D., passed away peacefully on May 15, 2023, after a recurrence of a previous illness. His contributions to the field earned him numerous awards and recognitions, including the industry's highest honor, the American Society of Transplant Surgeon's distinguished Pioneer Award. At the University of Wisconsin Madison Dr. Sollinger worked tirelessly on a gene therapy approach with the potential to revolutionize the treatment of type 1 diabetes mellitus T1DM. In 2016, after 20 years of research, he founded Endsulin, an early-stage biotech company based on Dr. Sollinger's proprietary technology. Endsulin is developing a single dose, liver-directed gene therapy that enables liver cells to produce and regulate insulin, mimicking the function of the pancreas. "The passing of Hans is a profound loss," said Endsulin's Chairman of the Board and CEO, Thomas Dee. "He was a true visionary and world leader in diabetes research whose personal interest in improving diabetes care led to remarkable achievements in pancreas transplantation, the development of immunosuppression, and discovery of a gene therapy in development for T1DM. On behalf of our Board of Directors, we extend our deepest, heartfelt condolences with the Sollinger family during this difficult time. At Endsulin we will honor Hans' legacy by exhibiting his energy, passion, and ambition in everything we do to further the development of our lead candidate ENS-101, which has the potential to reach millions of patients suffering with T1D." About Endsulin Endsulin is a pre-clinical stage gene therapy company whose mission is to end insulin dependence for good and free people from being defined by diabetes. Endsulin's approach employs a widely studied and proven viral vector to deliver their patented genetic factor to the liver and restore the body's own ability to produce and regulate insulin. With a single administration, Endsulin's revolutionary genetic therapy for T1DM delivers a patented genetic factor that will "switch on" new insulin-producing cells to confer years – and perhaps a lifetime – of freedom from injecting artificial insulin, realizing the goal that has eluded researchers since the discovery of insulin. Founded by an award-winning transplant surgeon and world leader in diabetes care and supported by a team of experts in gene therapy, endocrinology, diabetes science and pharmaceutical development, Endsulin has the scientific, medical, and commercial expertise to develop its innovative therapy quickly, filling an enormous unmet need and bringing us one step closer to ending insulin dependence for good — and for the good of everyone with T1DM. Media Contact: Julie Ferguson [email protected] (312)385-0098 SOURCE Endsulin

基因疗法高管变更

100 项与 EVT-101 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB05956

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
重度抑郁症	临床2期	-	Evotec SE	-
重度抑郁症	临床2期	-	F. Hoffmann-La Roche Ltd.	-
难治性抑郁症	临床申请批准	美国	Hoffmann-La Roche, Inc.	2010-06-01
难治性抑郁症	临床申请批准	美国	Janssen Research & Development LLC	2010-06-01