英文名称 | GTS-21 |
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别名 | DMBX-A |
英文别名 | DMBX-A |
IUPAC Name | 3-[(5E)-5-[(2,4-dimethoxyphenyl)methylidene]-3,4-dihydro-2H-pyridin-6-yl]pyridine |
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INCHI | InChI=1S/C19H20N2O2/c1-22-17-8-7-14(18(12-17)23-2)11-15-5-4-10-21-19(15)16-6-3-9-20-13-16/h3,6-9,11-13H,4-5,10H2,1-2H3/b15-11+ |
InChi Key | RPYWXZCFYPVCNQ-RVDMUPIBSA-N |
Canonical SMILES | COC1=CC(=C(C=C1)C=C2CCCN=C2C3=CN=CC=C3)OC |
PubChem CID | 5310985 |
分子量 | 308.37 |
PubChem CID | 5310985 |
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RCSB PDB Ligand | ZY7 |
CAS Registry No. | 148372-04-7 |
ChEMBL Ligand | CHEMBL134713 |
Ligand ID | 11384 |
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名称 | GTS-21 |
别名 | DMBX-A |
类别 | Synthetic organic |
学名 | 3-[(5E)-5-[(2,4-dimethoxyphenyl)methylidene]-3,4-dihydro-2H-pyridin-6-yl]pyridine |
生物活性评价 |
The sulfonamide class of antibacterial compounds are primarily bacteriostatic agents and have a broad spectrum of activity against both Gram-positive and Gram-negative species of bacteria (reviewed in |
评价 |
GTS-21 (DMBX-A), is a novel, small-molecule, orally active and selective α7 nicotinic acetylcholine (nACh) receptor agonist, that has been advanced to clinical evaluation in a range of conditions |
临床描述 |
Obesity is a serious and growing health problem in the United States. Obesity is associated
with health problems such as type-2 diabetes and cardiovascular disease, leading to decreased
quality of life and increased mortality. Given the health and quality-of-life effects of
obesity, developing effective treatments clearly is an important goal.
This study plans to learn more about the effects of an investigational new drug (DMXB-A
(3-(2,4-dimethoxybenzylidene anabaseine)) and its effects on obesity. The study drug has
similar effects to nicotine. Since nicotine has been found to affect appetite, the
investigators are interested in studying effects of the study drug, which has some
similarities to nicotine, on how your brain responds to such things as pictures of food. The
study drug has not been approved by the Food and Drug Administration (FDA), and is considered
experimental.
The study hypothesis is that 3-2,4 dimethoxybenzylidene anabaseine (DMXB-A), an orally administered nicotinic cholinergic agonist, will improve attention and other neuropsychological dysfunctions in schizophrenia, leading to improved psychosocial outcome. A Double Blind, Placebo-Controlled Randomized Study to Compare the Safety and Tolerability of GTS-21 (25 Mg TID, 50 Mg TID, 75 Mg TID and 150 Mg TID) When Administered Daily for 28 Days to Participants With Probable Alzheimer's Disease This study will be a randomized, double-blind, placebo-controlled crossover study to assess the effects of GTS21 (25 mg three times a day (tid), 75 mg tid, 150 mg tid) compared to placebo in non-smoking adults aged 18-55 with a diagnosis of ADHD, any subtype. Rationale: The vagus nerve exerts an anti-inflammatory effect in in vitro and animal experiments. This 'vagal anti-inflammatory pathway' is mediated by the nicotinergic α7nACh receptor that can be selectively stimulated by GTS-21. Activation of the cholinergic anti-inflammatory pathway via vagus nerve stimulation or α7nAChR agonists improves outcome in animal models of endotoxemia, sepsis and experimental arthritis. Up to now, the anti-inflammatory effects of oral administration of GTS-21 in humans in vivo has not been investigated. Objective: Primary aim: to investigate the anti-inflammatory effects of oral administration of GTS-21 on the inflammatory response in the human endotoxemia model and the subsequent inflammation-induced subclinical organ dysfunction. Secondary aim: to measure the effect of LPS administration in the absence or presence of GTS-21 in human volunteers on vagal nerve activity measured by heart rate variability analysis. Study design: Double-blind placebo-controlled randomized cross-over intervention study in healthy human volunteers during experimental endotoxemia. Study population: Non-smoking healthy male volunteers, age 18-35 yrs Intervention: Subjects will be tested in a cross-over design in 2 separate sequential sessions, 2-4 weeks apart. A total of 12 subjects will be randomly assigned to one of two dosing groups in a 1:1 ratio: GTS-21 followed by Placebo n=6, Placebo followed by GTS-21 n=6. Subjects will receive 150mg GTS-21 or placebo orally tid 3 days before LPS injection and an oral dose of 150 mg GTS-21 or placebo the morning of the day of LPS administration (07:00 AM). Subjects will then receive an oral dose of 150 mg GTS-21 or placebo at 08:00 AM and another oral dose of 150 mg GTS-21 or placebo at 1 hour before LPS administration (t=0). Before LPS injection, prehydration will be performed by infusion of 1.5 L 2.5% glucose/0.45% saline solution in 1 hour. One hour after the last dose of GTS-21 or placebo, LPS derived from E coli O:113 will be injected (2 ng/kg iv in 1 minute). There will be a 14 day washout period for patients in all groups. The last group of subjects will be subjected to an identical dose of LPS and placebo at two different moments 2-4 weeks apart to obtain time controls. Main study parameters/endpoints: Main study endpoint is the concentration of circulating cytokines after LPS in the absence and presence of GTS-21. Nature and extent of the burden and risks associated with participation, benefit and group relatedness: A medical interview and physical examination is part of this study. Approximately 350 ml blood will be withdrawn and urine will be collected. There will be mild discomfort associated with participation in this study, as LPS induces flu-like symptoms for approximately 4 hrs. GTS-21 was found to be well tolerated at a dose of 150 mg three times daily (450 mg/day). |
来源公司 |
University of Colorado, Denver University of Colorado, Denver CoMentis CoMentis Radboud University |
1. Xie H, Yepuri N, Meng Q, Dhawan R, Leech CA, Chepurny OG, Holz GG, Cooney RN. (2020) Therapeutic potential of α7 nicotinic acetylcholine receptor agonists to combat obesity, diabetes, and inflammation.. Rev Endocr Metab Disord, 21 (4): (431-447). [PMID:32851581] |
2. Garg BK, Loring RH. (2019) GTS-21 has cell-specific anti-inflammatory effects independent of α7 nicotinic acetylcholine receptors.. PLoS One, 14 (4): (e0214942). [PMID:30947238] |