By sarms4muscle.com | 25 May 2023 | 0 Comments
Glypromate neuropeptides: a new drug born from a methyl modification
Glypromate (also known as glycine-proline-glutamate, or GPE), an endogenous neuropeptide, is formed from IGF-1, a neurotrophic and anti-apoptotic brain-produced hormone that is crucial for healthy growth, metabolism, and damage repair.Glypromate is created after IGF-1 has been processed by acid proteases and is identical to the N-terminal sequence of IGF-1.
Glypromate neuropeptide may be implicated in regulating inflammation, promoting astrocytosis, inhibiting apoptosis, and limiting vascular remodeling, among other biological functions and potential therapeutic purposes, while its exact mechanism of action is unclear. Glypromate's usage is constrained by two key limitations, though: 1) It cannot be administered orally; 2) Its half-life in human plasma is only 30 minutes and it is metabolized by carboxypeptidase to cGP (a neuroprotective metabolite) and glutamate. It is consequently designed to enhance the pharmacokinetic profile of glycomate, which includes blood-brain barrier permeability, metabolic stability (raising biochemical resistance to serum proteases), and oral bioavailability. Figure 1 displays a summary of the six optimization strategies.
1. Modification of proline residues
In comparison to Glypromate, the -methyl derivative15 (also known as Trofinetide or NNZ-2566) exhibits better pharmacokinetic properties, such as an improved half-life and oral bioavailability, increased resistance to enzymatic degradation, and effective anti-inflammatory and anti-apoptotic properties.
2. Modification of glycine residues
Compounds 1 to 5 were able to improve lipophilicity and metabolic stability in comparison to the parent neuropeptides.
3. Modification of glutamate residues
4. Pseudotripeptide analogs
The inclusion of amide-bonded allelochemicals (aminomethylene units) improved metabolic stability. While Glypromate had a half-life of just 30 min in human plasma, compound 78 (11.8 h) had the longest plasma half-life, followed by compounds 76 (6.6 h) and 77 (4.5 h).
5. Cyclic and macrocyclic analogs
6. Glycopropionate coupling compound
Including dimethyl glycine propionate-lipoic acid conjugate, polyethylene glycol glycine propionate, Glypromate-Peracetylated L/D configuration-DOPA coupling and amphiphilic derivatives of glycinamide.
7. NNZ-2591, cGP analogue
A cGP analog made by Neuren Pharmaceuticals is called NNZ-2591.For the treatment of Phelan-McDermid syndrome, Angelman syndrome, Pitt-Hopkins syndrome, and Prader-Willi syndrome, NNZ-2591 has received FDA approval to begin phase 2 clinical studies [2].
8. Trofinetide, proline-modified analogue
As part of their investigation into potential molecules for the treatment of traumatic brain injury, Brimble's team at the University of Auckland in New Zealand discovered trofinetide (molecule 15) in 2002. Since then, trofinetide has been studied by Neuren Pharmaceuticals and Acadia Pharmaceuticals for a number of neurological diseases [2]. Trofinetide's metabolic resistance to protease activity was greatly boosted by the methyl substitution of the proline's proton, leading to an extended half-life. Trofinetide has been demonstrated to boost synaptic plasticity signals and dendritic branching in animal tests.
The FDA granted tropinetide (oral solution) approval for the treatment of Rett syndrome patients 2 years of age and older in March 2023.Rett syndrome is a complicated, uncommon neurodevelopmental illness that is often brought on by a genetic mutation in the MECP2 gene. It has been demonstrated that this abnormality impairs synaptic connection.Rett syndrome is characterized by a period of normal development lasting between six and eighteen months, followed by a major regress in development, as shown by an impasse in the development of motor skills and communicative abilities. As shown by developmental pauses in motor control and communicative abilities, Rett syndrome is characterized by a period of normal growth lasting from 6 to 18 months, followed by a considerable developmental regression.In the United States, Rett syndrome has been identified in about 4,500 people [3].
Reference:
[1] Classics in Chemical Neuroscience: Aripiprazole. ACS Chem. Neurosci. 2023, 14, 554–572.
[2]https://www.auckland.ac.nz/en/news/2023/03/11/margaret-brimble-trofinetide-wins-FDA-approval.html
[3]https://acadia.com/media/news-releases/acadia-pharmaceuticals-announces-u-s-fda-approval-of-daybue-trofinetide-for-the-treatment-of-rett-syndrome-in-adult-and-pediatric-patients-two-years-of-age-and-older/
Glypromate neuropeptide may be implicated in regulating inflammation, promoting astrocytosis, inhibiting apoptosis, and limiting vascular remodeling, among other biological functions and potential therapeutic purposes, while its exact mechanism of action is unclear. Glypromate's usage is constrained by two key limitations, though: 1) It cannot be administered orally; 2) Its half-life in human plasma is only 30 minutes and it is metabolized by carboxypeptidase to cGP (a neuroprotective metabolite) and glutamate. It is consequently designed to enhance the pharmacokinetic profile of glycomate, which includes blood-brain barrier permeability, metabolic stability (raising biochemical resistance to serum proteases), and oral bioavailability. Figure 1 displays a summary of the six optimization strategies.
1. Modification of proline residues
In comparison to Glypromate, the -methyl derivative15 (also known as Trofinetide or NNZ-2566) exhibits better pharmacokinetic properties, such as an improved half-life and oral bioavailability, increased resistance to enzymatic degradation, and effective anti-inflammatory and anti-apoptotic properties.
2. Modification of glycine residues
Compounds 1 to 5 were able to improve lipophilicity and metabolic stability in comparison to the parent neuropeptides.
3. Modification of glutamate residues
4. Pseudotripeptide analogs
The inclusion of amide-bonded allelochemicals (aminomethylene units) improved metabolic stability. While Glypromate had a half-life of just 30 min in human plasma, compound 78 (11.8 h) had the longest plasma half-life, followed by compounds 76 (6.6 h) and 77 (4.5 h).
5. Cyclic and macrocyclic analogs
6. Glycopropionate coupling compound
Including dimethyl glycine propionate-lipoic acid conjugate, polyethylene glycol glycine propionate, Glypromate-Peracetylated L/D configuration-DOPA coupling and amphiphilic derivatives of glycinamide.
7. NNZ-2591, cGP analogue
A cGP analog made by Neuren Pharmaceuticals is called NNZ-2591.For the treatment of Phelan-McDermid syndrome, Angelman syndrome, Pitt-Hopkins syndrome, and Prader-Willi syndrome, NNZ-2591 has received FDA approval to begin phase 2 clinical studies [2].
8. Trofinetide, proline-modified analogue
As part of their investigation into potential molecules for the treatment of traumatic brain injury, Brimble's team at the University of Auckland in New Zealand discovered trofinetide (molecule 15) in 2002. Since then, trofinetide has been studied by Neuren Pharmaceuticals and Acadia Pharmaceuticals for a number of neurological diseases [2]. Trofinetide's metabolic resistance to protease activity was greatly boosted by the methyl substitution of the proline's proton, leading to an extended half-life. Trofinetide has been demonstrated to boost synaptic plasticity signals and dendritic branching in animal tests.
The FDA granted tropinetide (oral solution) approval for the treatment of Rett syndrome patients 2 years of age and older in March 2023.Rett syndrome is a complicated, uncommon neurodevelopmental illness that is often brought on by a genetic mutation in the MECP2 gene. It has been demonstrated that this abnormality impairs synaptic connection.Rett syndrome is characterized by a period of normal development lasting between six and eighteen months, followed by a major regress in development, as shown by an impasse in the development of motor skills and communicative abilities. As shown by developmental pauses in motor control and communicative abilities, Rett syndrome is characterized by a period of normal growth lasting from 6 to 18 months, followed by a considerable developmental regression.In the United States, Rett syndrome has been identified in about 4,500 people [3].
Reference:
[1] Classics in Chemical Neuroscience: Aripiprazole. ACS Chem. Neurosci. 2023, 14, 554–572.
[2]https://www.auckland.ac.nz/en/news/2023/03/11/margaret-brimble-trofinetide-wins-FDA-approval.html
[3]https://acadia.com/media/news-releases/acadia-pharmaceuticals-announces-u-s-fda-approval-of-daybue-trofinetide-for-the-treatment-of-rett-syndrome-in-adult-and-pediatric-patients-two-years-of-age-and-older/
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