Discovery of a <i>para</i>-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain

Rais, Rana; Vávra, Jan; Tichý, Tomáš; Dash, Ranjeet Prasad; Gadiano, Alexandra J.; Tenora, Lukáš; Monincová, Lenka; Bařinka, Cyril; Alt, Jesse; Zimmermann, Sarah C.; Slusher, C. Ethan; Wu, Ying; Wozniak, Krystyna M.; Majer, Pavel; Tsukamoto, Takashi; Slusher, Barbara S.

doi:10.1021/acs.jmedchem.7b00825

Cited by 25 publications

(20 citation statements)

References 20 publications

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“…Masking hydroxamic acids was recently reported as an approach to overcome problems like fast elimination, decreased cellular uptake and poor tissue penetration caused by the highly polar hydroxamic acid group [85][86][87][88][89][90]. In addition, paraacetoxybenzyl-based prodrugs were shown to be completely converted to the parent hydroxamic acid in plasma [91]. Unfortunately, even these masked hydroxamic acids 59a,b and 60b (log P values ranging from 2.51-3.08, calculated with ChemDraw Ultra 8) did not show an improvement in the activity against either THP-1 or HL60 cell lines.…”

Section: Cellular Assaymentioning

confidence: 99%

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Ghazy

Zeyen

Herp

et al. 2020

European Journal of Medicinal Chemistry

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Histone modifying proteins, specifically histone deacetylases (HDACs) and bromodomains, have emerged as novel promising targets for anticancer therapy. In the current work, based on available crystal structures and docking studies, we designed dual inhibitors of both HDAC6/8 and the bromodomain and PHD finger containing protein 1 (BRPF1). Biochemical and biophysical tests showed that compounds 23a,b and 37 are nanomolar inhibitors of both target proteins. Detailed structure-activity relationships were deduced for the synthesized inhibitors which were supported by extensive docking and molecular dynamics studies. Cellular testing in acute myeloid leukemia (AML) cells showed only a weak effect, most probably because of the poor permeability of the inhibitors. We also aimed to analyse the target engagement and the cellular activity of the novel inhibitors by determining the protein acetylation levels in cells by western blotting (tubulin vs histone acetylation), and by assessing their effects on various cancer cell lines.

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Section: Cellular Assaymentioning

confidence: 99%

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Ghazy

Zeyen

Herp

et al. 2020

European Journal of Medicinal Chemistry

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“…In both model systems extracellular NAAG concentration is increased (Zhang et al, 2006;Neale & Yamamoto, 2020). These studies provided strong evidence that NAAG is neuroprotective, has analgesic effects in connection with inflammatory as well as neuropathic pain, and attenuates peripheral neuropathy (Yamamoto et al, 2004(Yamamoto et al, , 2007Wozniak et al, 2012;Vornov et al, 2013;Rais et al, 2017; for review: Vornov et al 2016). Furthermore, there is also strong evidence that NAAG plays an important role in memory and cognition (for review: Neale & Yamamoto, 2020).…”

Section: Introductionmentioning

confidence: 99%

Mice deficient in the NAAG synthetase II gene Rimkla are impaired in a novel object recognition task

Becker

Wang-Eckhardt

Lodder-Gadaczek

et al. 2021

Journal of Neurochemistry

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N‐acetylaspartylglutamate (NAAG) is an abundant neuropeptide in the mammalian nervous system, synthesized by two related NAAG synthetases I and II (NAAGS‐I and ‐II) encoded by the genes Rimklb and Rimkla, respectively. NAAG plays a role in cognition and memory, according to studies using inhibitors of the NAAG hydrolase glutamate carboxypeptidase II that increase NAAG concentration. To examine consequences of reduced NAAG concentration, Rimkla‐deficient (Rimkla−/−) mice were generated. These mice exhibit normal NAAG level at birth, likely because of the intact Rimklb gene, but have significantly reduced NAAG levels in all brain regions in adulthood. In wild type mice NAAGS‐II was most abundant in brainstem and spinal cord, as demonstrated using a new NAAGS‐II antiserum. In the hippocampus, NAAGS‐II was only detectable in neurons expressing parvalbumin, a marker of GABAergic interneurons. Apart from reduced open field activity, general behavior of adult (6 months old) Rimkla−/− mice examined in different tests (dark‐light transition, optokinetic behavior, rotarod, and alternating T‐maze) was not significantly altered. However, Rimkla−/− mice were impaired in a short‐term novel object recognition test. This was also the case for mice lacking NAA synthase Nat8l, which are devoid of NAAG. Together with results from previous studies showing that inhibition of the NAAG degrading enzyme glutamate carboxypeptidase II is associated with a significant improvement in object recognition, these results suggest a direct involvement of NAAG synthesized by NAAGS‐II in the memory consolidation underlying the novel object recognition task.

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“…Glutamate production, to which this enzyme contributes, is a basis of this important neurotransmitter, and might be an alternative to inhibition of receptors for glutamate [613]. Mice deficient of this enzyme had less neuropathic pain [614], and an orally available antagonist for this enzyme reduced neuropathic pain [615].…”

Section: Glutamate Carboxypeptidase IImentioning

confidence: 99%

Novel Analgesics with Peripheral Targets

Ciotu

Fischer

2020

Neurotherapeutics

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A limited number of peripheral targets generate pain. Inflammatory mediators can sensitize these. The review addresses targets acting exclusively or predominantly on sensory neurons, mediators involved in inflammation targeting sensory neurons, and mediators involved in a more general inflammatory process, of which an analgesic effect secondary to an anti-inflammatory effect can be expected. Different approaches to address these systems are discussed, including scavenging proinflammatory mediators, applying anti-inflammatory mediators, and inhibiting proinflammatory or facilitating anti-inflammatory receptors. New approaches are contrasted to established ones; the current stage of progress is mentioned, in particular considering whether there is data from a molecular and cellular level, from animals, or from human trials, including an early stage after a market release. An overview of publication activity is presented, considering a IuPhar/BPS-curated list of targets with restriction to pain-related publications, which was also used to identify topics.

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Discovery of a para-Acetoxy-benzyl Ester Prodrug of a Hydroxamate-Based Glutamate Carboxypeptidase II Inhibitor as Oral Therapy for Neuropathic Pain

Cited by 25 publications

References 20 publications

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Design, synthesis, and biological evaluation of dual targeting inhibitors of histone deacetylase 6/8 and bromodomain BRPF1

Mice deficient in the NAAG synthetase II gene Rimkla are impaired in a novel object recognition task

Novel Analgesics with Peripheral Targets

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