EVT 101 News - LARVOL Sigma

|||||||||| ifenprodil tartrate / Chiba University Hospital, EVT 101 / J&J
Journal: Discovery of novel tryptamine derivatives as GluN2B subunit-containing NMDA receptor antagonists via pharmacophore-merging strategy with orally available therapeutic effect of cerebral ischemia. (Pubmed Central) - Apr 25, 2023
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). 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

|||||||||| ifenprodil tartrate / Chiba University Hospital, EVT 101 / J&J
Journal: Biphenyl scaffold for the design of NMDA-receptor negative modulators: molecular modeling, synthesis, and biological activity. (Pubmed Central) - Aug 6, 2022
Preliminary calculation results suggest a low affinity for the human ether-a-go-go-related gene ion channel (hERG), a high affinity for which was earlier one of the main obstacles for the development of first-generation NMDA-receptor negative allosteric modulators. The docking study and the molecular dynamics calculations suggest a completely different binding mode (ifenprodil-like) compared to another biaryl-based NMDA NAM EVT-101.

|||||||||| Review, Journal: Novel Glutamatergic Modulators for the Treatment of Mood Disorders: Current Status. (Pubmed Central) - Jan 7, 2022
Furthermore, to date, most have demonstrated relatively modest effects compared with (R,S)-ketamine and esketamine, though some have shown more favorable characteristics. Of these novel agents, the most promising, and the ones for which the most evidence exists, appear to be those targeting ionotropic glutamate receptors.

|||||||||| ifenprodil tartrate / Chiba University Hospital, EVT 101 / J&J
Preclinical, Journal: Repurposing of cefpodoxime proxetil as potent neuroprotective agent through computational prediction and in vitro validation. (Pubmed Central) - Aug 13, 2021
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 Ca influx induced by NMDA were applied to validate the computational results, further investigation showed that 5 could suppress the NR2B upregulation induced by NMDA.

|||||||||| risperidone / Generic mfg., dextromethorphan / Generic mfg.
Preclinical, Journal: 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. (Pubmed Central) - Jun 22, 2021
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...The in silico modeling of dextromethorphan against PPDA, TCN-201, MK-22, EVT-101 on NMDA receptors was also performed...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.

|||||||||| EVT 101 / J&J
Review, Journal: A comprehensive description of GluN2B-selective N-methyl-D-aspartate (NMDA) receptor antagonists. (Pubmed Central) - Feb 5, 2021
And the latter are further divided into amidine derivatives, 4-aminoquinolines, indole derivatives, benzimidazole derivatives, oxamide derivatives, carbamate derivatives, EVT-101 analogues, 1H-pyrrolo[3,2-b]pyridine derivatives, benzazepin derivatives, other heterocyles and radiotracers. This review will provide a comprehensive description including structure, structure-activity relationship (SAR), and pharmacology of novel GluN2B-subtype selective NMDA antagonists to the medicinal chemists, which would be helpful in rational designing effective drugs aimed toward related CNS disease.

|||||||||| memantine / Generic mfg.
Journal: Functional and pharmacological properties of triheteromeric GluN1/2B/2D NMDA receptors. (Pubmed Central) - Sep 9, 2020
•GluN2B-selective antagonists produce robust inhibition of GluN1/2B/2D receptors, and the GluN2B-selective positive allosteric modulator spermine enhances responses from GluN1/2B/2D, but not GluN1/2A/2B receptors. •These insights to the properties of triheteromeric GluN1/2B/2D receptors are necessary to appreciate their physiological roles in neural circuit function and the actions of therapeutic agents targeting NMDA receptors.

|||||||||| ifenprodil tartrate / Chiba University Hospital, EVT 101 / J&J
Journal: Computational investigation of the antagonism effect towards GluN2B-Containing NMDA receptor: Combined ligand-based and target-based approach. (Pubmed Central) - Feb 22, 2020
Which results in the proposal of two interaction models inside the GluN2B binding cavity for two groups of antagonists. The interaction model of "ifenprodil group" antagonists consists of one hydrophobic group, one H-bond donor, one H-bond acceptor and an aromatic ring, while on the other hand, the interaction model of "EVT101 group" antagonists includes three hydrophobic groups and an aromatic ring.

|||||||||| ifenprodil tartrate / Chiba University Hospital, EVT 101 / J&J
Preclinical, Journal: Exploring the overlapping binding sites of ifenprodil and EVT-101 in GluN2B-containing NMDA receptors using novel chicken embryo forebrain cultures and molecular modeling. (Pubmed Central) - Feb 9, 2020
The EVT-101 binding pocket appears to accommodate more structurally different ligands than the ifenprodil-binding site, and contains residues essential in ligand interactions necessary for calcium influx inhibition. For the ifenprodil site, the less effective antagonist (eliprodil) fails to interact with key residues, while in the EVT-101 pocket, difference in potency might be explained by differences in ligand-receptor interaction patterns.

|||||||||| ganaxolone oral (CCD-1042) / Marinus
Review, Journal: A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems. (Pubmed Central) - Aug 3, 2019
Here, we review progress in the development of compounds that act on these systems as well as their purported mechanisms of action. We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217.

||||||||||  EVT 101 / J&J
Enrollment change, Monotherapy:  Safety and Efficacy of EVT 101 in Treatment-Resistant Depression (clinicaltrials.gov) -  Dec 30, 2015
P2, N=8, Terminated,  Sponsor: Janssen Research & Development, LLC
We include glutamate-targeting drugs, such as racemic ketamine, esketamine, lanicemine (AZD6765), traxoprodil (CP-101,606), EVT-101, rislenemdaz (CERC-301/MK-0657), AVP-786, AXS-05, rapastinel (formerly GLYX-13), apimostinel (NRX-1074/AGN-241660), AV-101, NRX-101, basimglurant (RO4917523), decoglurant (RG-1578/RO4995819), tulrampator (CX-1632/S-47445), and riluzole; and GABA-targeting agents, such as brexanolone (SAGE-547), ganaxolone, and SAGE-217. N=14 --> 8

||||||||||  EVT 101 / J&J
Enrollment change, Monotherapy:  Safety and Efficacy of EVT 101 in Treatment-Resistant Depression (clinicaltrials.gov) -  Feb 24, 2013
P2, N=14, Terminated,  Sponsor: Evotec Neurosciences GmbH
N=14 --> 8 N=100 --> 14

||||||||||  EVT 101 / J&J
Trial termination, Monotherapy:  Safety and Efficacy of EVT 101 in Treatment-Resistant Depression (clinicaltrials.gov) -  Sep 7, 2011
P2, N=14, Terminated,  Sponsor: Evotec Neurosciences GmbH
N=100 --> 14 Recruiting --> Terminated; Evotec has indicated that this study was discontinued due to a clinical hold issued by the FDA



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