Discovery and lead optimisation of a potent, selective and orally bioavailable RARβ agonist for the potential treatment of nerve injury (original) (raw)
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Biomedical features and therapeutic potential of rosmarinic acid
Archives of Pharmacal Research
provide state-of-the-art, flexible therapeutic potential and biomedical features of RA, its implications and multiple uses. Along with various valuable applications in safeguarding human health, this review further summarizes the therapeutic advantages of RA in various human diseases, including cancer, diabetes, neurodegenerative diseases. Furthermore, the challenges associated with the clinical applicability of RA have also been discussed.
Bioorganic & Medicinal Chemistry, 2013
In silico study Synthetic scale-up Physicochemical properties Metabolic stability a b s t r a c t Strong pharmacological evidences indicate that r1 receptors are implicated in the pathophysiology of all major CNS disorders. In the last years our research group has conducted extensive studies aimed at discovering novel r1 ligands and we recently selected (R/S)-RC-33 as a novel potent and selective r1 receptor agonist. As continuation of our work in this field, here we report our efforts in the development of this new r1 receptor agonist. Initially, we investigated the binding of (R) and (S) enantiomers of RC-33 to the r1 receptor by in silico experiments. The close values of the predicted affinity of (R)-RC-33 and (S)-RC-33 for the protein evidenced the non-stereoselective binding of RC-33 to the r1 receptor; this, in turn, supported further development and characterization of RC-33 in its racemic form. Subsequently, we set-up a scaled-up, optimized synthesis of (R/S)-RC-33 along with some compound characterization data (e.g., solubility in different media and solid state characterization by thermal analysis techniques). Finally, metabolic studies of RC-33 in different biological matrices (e.g., plasma, blood, and hepatic S9 fraction) of different species (e.g., rat, mouse, dog, and human) were performed. (R/S)-RC-33 is generally stable in all examined biological matrices, with the only exception of rat and human liver S9 fractions in the presence of NADPH. In such conditions, the compound is subjected to a relevant oxidative metabolism, with a degradation of approximately 65% in rat and 69% in human.
Frontiers in Cellular Neuroscience
Axon regeneration after peripheral nerve injury is slow and inefficient, leading to generally poor functional recovery. Activity-dependent experimental therapies that increase expression of brain-derived neurotrophic factor (BDNF) and its TrkB receptors enhance regeneration, suggesting that treatments with BDNF might also be effective. However, recombinant human BDNF (rhBDNF), as well as 7,8-dihydroxyflavone (7,8-DHF), a small molecular BDNF mimetic, may have limited treatment applications because of their modest oral bioavailability and pharmacokinetic profile. R13 is a 7,8-DHF prodrug. Upon oral administration, it is converted in the liver to 7,8-DHF. In immunoblots from tissues at the site of nerve injury, a single oral treatment with R13 to mice following sciatic nerve transection and repair produced a rapid and prolonged increase in immunoreactivity to phosphorylated TrkB, prolonged phosphorylation of mitogen activated protein kinase (MAPK/Erk1/2), and a rapid but transient inc...
Importance and hurdles to drug discovery for neurological disease
Annals of Neurology, 2013
This is a critical time in neurotherapeutics. The prevalence of neurological disease, such as dementia, stroke, and peripheral neuropathy, is large and growing consequent to the aging population. The personal and societal impact of these disorders is enormous, and the number of novel therapies in the pipeline for these disorders has been contracting. Support for the development of neurotherapies must continue from the bench to their ultimate place at the bedside. Academic medicine must continue to play a critical role, in league with industry and government, in the development of novel neurotherapies desperately needed by an ever-expanding population. Critical steps include the identification and adoption of reliable, valid, and reproducible biomarkers to serve as primary endpoints in clinical trials of neurological disease.
Experimental Neurology, 2008
Treatment of degenerating basal forebrain cholinergic neurons with nerve growth factor (NGF) in Alzheimer's disease has long been contemplated, but an effective and safe delivery method has been lacking. Towards achieving this goal, we are currently developing CERE-110, an adeno-associated virus-based gene delivery vector that encodes for human NGF, for stereotactic surgical delivery to the human nucleus basalis of Meynert. Results indicate that NGF transgene delivery to the targeted brain region via CERE-110 is reliable and accurate, that NGF transgene distribution can be controlled by altering CERE-110 dose, and that it is possible to achieve restricted NGF expression limited to but covering the target brain region. Results from animals examined at longer time periods of 3, 6, 9 and 12 months after CERE-110 delivery indicate that NGF transgene expression is stable and sustained at all time points, with no loss or build-up of protein over the long-term. In addition, results from a series of experiments indicate that CERE-110 is neuroprotective and neurorestorative to basal forebrain cholinergic neurons in the rat fimbria-fornix lesion and aged rat models, and has bioactive effects on young rat basal forebrain cholinergic neurons. These findings, as well as those from several additional nonclinical experiments conducted in both rats and monkeys, led to the initiation of a Phase I clinical study to evaluate the safety and efficacy of CERE-110 in Alzheimer's disease subjects, which is currently ongoing.
Targeting the innate repair receptor to treat neuropathy
PAIN Reports, 2016
The innate repair receptor (IRR) is a heteromer of the erythropoietin receptor and the b-common (CD131) receptor, which simultaneously activates anti-inflammatory and tissue repair pathways. Experimental data suggest that after peripheral nerve injury, the IRR is upregulated in the spinal cord and modulates the neurogenic inflammatory response. The recently introduced selective IRR agonist ARA290 is an 11-amino acid peptide initially tested in animal models of neuropathy. After sciatic nerve injury, ARA290 produced a rapid and long-term relief of mechanical and cold allodynia in normal mice, but not in animals with a b-common receptor knockout phenotype. In humans, ARA290 has been evaluated in patients with small fiber neuropathy associated with sarcoidosis or type 2 diabetes (T2D) mellitus. In patients with sarcoidosis, ARA290 significantly improved neuropathic and autonomic symptoms, as well as quality of life as assessed by the small fiber neuropathy screening list questionnaire. In addition, ARA290 treatment for 28 days initiated a regrowth of small nerve fibers in the cornea, but not in the epidermis. In patients with T2D, the results were similar to those observed in patients with sarcoidosis along with an improved metabolic profile. In both populations, ARA290 lacked significant adverse effects. These experimental and clinical studies show that ARA290 effectively reprograms a proinflammatory, tissue-damaging milieu into one of healing and tissue repair. Further clinical trials with long-term treatment and follow-up are needed to assess the full potential of IRR activation by ARA290 as a disease-modifying therapy in neuropathy of various etiologies.
The importance and hurdles to drug discovery for neurological disease
Annals of Neurology, 2013
This is a critical time in neurotherapeutics. The prevalence of neurological disease, such as dementia, stroke, and peripheral neuropathy, is large and growing consequent to the aging population. The personal and societal impact of these disorders is enormous, and the number of novel therapies in the pipeline for these disorders has been contracting. Support for the development of neurotherapies must continue from the bench to their ultimate place at the bedside. Academic medicine must continue to play a critical role, in league with industry and government, in the development of novel neurotherapies desperately needed by an ever-expanding population. Critical steps include the identification and adoption of reliable, valid, and reproducible biomarkers to serve as primary endpoints in clinical trials of neurological disease.
Bioorganic & Medicinal Chemistry, 2012
The transient receptor potential ankyrin 1 (TRPA1) channel is activated by a series of by-products of oxidative/nitrative stress, produced under inflammatory conditions or in the case of tissue damage, thus generating inflammatory and neuropathic pain and neurogenic inflammatory responses. These findings have identified TRPA1 as an emerging opportunity for the design and synthesis of selective inhibitors as potential analgesic and antiinflammatory agents. Herein we present the synthesis and functional evaluation of a new series of 7-substituted-1,3-dimethyl-1,5-dihydro-pyrrolo[3,2-d]pyrimidine-2,4-dione derivatives designed as TRPA1 antagonists. A small library of compounds has been built by the introduction of differently substituted N 7 -phenylacetamide or N 7 -[4-(substituted-phenyl)-thiazol-2-yl]acetamide chains. All the synthesized compounds were assayed to evaluate their ability to block acrolein-mediated activation of native human and rat TRPA1 channels employing a fluorometric calcium imaging assay. Our study led us to the identification of compound 3h which showed considerably improved potency (IC 50 = 400 nM) against human TRPA1 with regard to some of the most representative antagonists previously reported and integrated in our screening program as reference compounds. In addition, 3h proved to maintain its efficacy toward rTRPA1, which designates it as a possible candidate for future evaluation of in vivo efficacy in rodent animal model of inflammatory and neuropathic pain.
Deciphering the therapeutical potentials of rosmarinic acid
Scientific Reports
Lemon balm is herbal tea used for soothing stomach cramps, indigestion, and nausea. Rosmarinic acid (RA) is one of its chemical constituents known for its therapeutic potentials against cancer, inflammatory and neuronal diseases such as the treatment of neurofibromatosis or prevention from Alzheimer’s diseases (AD). Despite efforts, recovery and purification of RA in high yields has not been entirely successful. Here, we report its aqueous extraction with optimal conditions and decipher the structure by nuclear magnetic resonance (NMR) spectroscopy. Using various physical–chemical and biological assays, we highlight its anti-aggregation inhibition potentials against the formation of Tau filaments, one of the hallmarks of AD. We then examine its anti-cancer potentials through reduction of the mitochondrial reductase activity in tumor cells and investigate its electrochemical properties by cyclic voltammetry. Our data demonstrates that RA is a prominent biologically active natural pro...
An update on pharmacological approaches to neurodegenerative diseases
Expert Opinion on Investigational Drugs, 2007
Neurodegenerative diseases are now generally considered as a group of disorders that seriously and progressively impair the functions of the nervous system through selective neuronal vulnerability of specific brain regions. Alzheimer's disease is the most common neurodegenerative disease, followed in incidence by Parkinson's disease; much less common are frontotemporal dementia, Huntington's disease, amyothrophic lateral sclerosis (Lou Gehrig's disease), progressive supranuclear palsy, spinocerebellar ataxia, Pick's disease and, lastly, prion disease. In this review, the authors intend to survey new drugs in different clinical phases but not in the preclinical or discovery stages nor already in the market, with new molecules aimed at interrupting or at attenuating different pathogenic pathways of neurodegeneration and/or at ameliorating symptoms. Drugs in different pharmacological phases are under study or are ready to be introduced into therapy for Alzheimer's disease, which display anti-β-amyloid activity or nerve growth factor-like activity or anti-inflammatory properties. Other drugs possess mixed mechanisms of action, such as acetylcholinesterase inhibition and impairment of β-amyloid formation through inhibition of β-amyloid precursor protein synthesis and/or modulation of secretase activity. Other therapeutic approaches are based on immunotherapy, control of metal ions interactions with β-amyloid and ensuing oxidative reactions as well as metabolic or hormonal regulation. The symptomatic therapy of motor behaviour in Parkinson's disease, based on L-DOPA, is registering adenosine A 2A receptor antagonists, monoamine oxidase B inhibitors and ion channel modulators, as well as dopamine uptake inhibitors and glutamate AMPA receptor antagonists. There are also many other drugs involved, including astrocyte-modulating agents, 5-HT 1A agonists and α 2-adrenergic receptor antagonists, which are targeted at preventing or ameliorating Parkinson's disease-related or L-DOPA-induced dyskinesias. Huntington's disease therapy envisages a Phase III drug, LAX-101, which displays antiapoptotic properties by promoting membrane stabilisation and mitochondrial integrity. Other drugs with antioxidant and antiapoptotic steroid-like and neuroprotective activity are under investigation for the therapy of the less common neurodegenerative diseases.