The discovery and structure–activity relationships of indole-based inhibitors of glutamate carboxypeptidase II

Grella, Brian; Adams, J.; Berry, James F.; Delahanty, Greg; Ferraris, Dana; Majer, Pavel; Ni, Chiyou; Shukla, Krupa H.; Shuler, Scott A.; Slusher, Barbara S.; Stathis, Marigo; Tsukamoto, Takashi

doi:10.1016/j.bmcl.2010.10.109

Cited by 12 publications

(8 citation statements)

References 13 publications

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“…Selecting the most suitable thiol-containing parent compound is therefore the crucial step in this particular prodrug approach. It is worth noting that the 5-mercaptopentanoic acid scaffold has been embedded in a variety of thiol-based GCPII inhibitors, ,,, which can be exploited in the search for δ-thiolactone prodrugs with superior pharmacological properties.…”

Section: Discussionmentioning

confidence: 99%

δ-Thiolactones as Prodrugs of Thiol-Based Glutamate Carboxypeptidase II (GCPII) Inhibitors

Ferraris

Majer

et al. 2013

J. Med. Chem.

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δ-Thiolactones derived from thiol-based glutamate carboxypeptidase II (GCPII) inhibitors were evaluated as prodrugs. In rat liver microsomes, 2-(3-mercaptopropyl)pentanedioic acid (2-MPPA, 1) was gradually produced from 3-(2-oxotetrahydro-thiopyran-3-yl)propionic acid (5), a thiolactone derived from 1. Compound 1 was detected in plasma at concentrations well above its IC50 value for GCPII following oral administration of 5 in rats. Consistent with the oral plasma pharmacokinetics, thiolactone 5 exhibited efficacy in a rat model of neuropathic pain following oral administration.

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Section: Discussionmentioning

confidence: 99%

δ-Thiolactones as Prodrugs of Thiol-Based Glutamate Carboxypeptidase II (GCPII) Inhibitors

Ferraris

Majer

et al. 2013

J. Med. Chem.

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“…Even though 2-MPPA did not provoke any adverse CNS effects and was well-tolerated at plasma concentrations, no additional studies were carried out because of the relatively low potency of 2-MPPA together with concerns over potential immune reactivity common to thiol-containing drugs [21]. Recently, a series of 3-(2mercaptoethyl)-1H-indole-2-carboxylic acid derivatives was reported as potent NAAG peptidase inhibitors [48]. The substituents on the indole nitrogen seem to have a significant influence on the activity of the ligands.…”

Section: Phosphonate-and Thiol-based Inhibitorsmentioning

confidence: 99%

Blockade ofN-acetylaspartylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders

Zhong

Luo

Jiang

2014

International Journal of Neuroscience

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The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress glutamate release mainly through selective activation of presynaptic Group II metabotropic glutamate receptor subtype 3 (mGluR3). Therefore, strategies of inhibition of NAAG peptidases and subsequent NAAG hydrolysis to elevate levels of NAAG could reduce glutamate release under pathological conditions and be neuroprotective by attenuating excitotoxic cell injury. A series of potent inhibitors of NAAG peptidases has been synthesized and demonstrated efficacy in experimental models of ischemic-hypoxic brain injury, traumatic brain injury, inflammatory pain, diabetic neuropathy, amyotrophic lateral sclerosis and phencyclidine-induced schizophrenia-like behaviors. The excessive glutamatergic transmission has been implicated in all of these neurological disorders. Thus, blockade of NAAG peptidases may augment an endogenous protective mechanism and afford neuroprotection in the brain. This review aims to summarize and provide insight into the current understanding of the novel neuroprotective strategy based on limiting glutamate excitotoxicity for a wide variety of brain injuries and neurological disorders.

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“…Tween 20 in very small amount was used as an emulsifier for making stock solution which was further diluted to make different concentrations. Distilled water was used to make control with addition of same amount of (Grella et al 2010). In addition to this, indole containing derivatives also possess promising cardiovascular activity (Singh et al 2013).…”

Section: Hatching Testmentioning

confidence: 99%

Synthesis of Indole Derivatives and Their Evaluation against Root Knot Nematode Meloidogyne incognita

Kaur

Utreja

Dhillon

et al. 2019

LOC

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Eight new 2-(1H-indol-3-yl)-N-(aryl)-2-oxoacetamide amine based indole derivatives were synthesized. Microanalytical data, 1HNMR, 13CNMR, FT-IR and XRD were used to characterize the synthesized derivatives. The indole derivatives had also been screened for their nematicidal activity against root-knot nematode Meloidogyne incognita. Chlorine substituted indole derivatives had shown significant nematicidal activity comparative to other indole derivatives.

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The discovery and structure–activity relationships of indole-based inhibitors of glutamate carboxypeptidase II

Cited by 12 publications

References 13 publications

δ-Thiolactones as Prodrugs of Thiol-Based Glutamate Carboxypeptidase II (GCPII) Inhibitors

δ-Thiolactones as Prodrugs of Thiol-Based Glutamate Carboxypeptidase II (GCPII) Inhibitors

Blockade ofN-acetylaspartylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders

Synthesis of Indole Derivatives and Their Evaluation against Root Knot Nematode Meloidogyne incognita

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