Riccaboni M.,NiKem Research |
Bianchi I.,NiKem Research |
Petrillo P.,NiKem Research
Drug Discovery Today | Year: 2010
Spleen tyrosine kinase (Syk) is an intriguing protein tyrosine kinase involved in signal transduction in a variety of cell types, and its aberrant regulation is associated with different allergic disorders and antibody-mediated autoimmune diseases such as rheumatoid arthritis, asthma and allergic rhinitis. Syk also plays an important part in the uncontrolled growth of tumor cells, particularly B cells. For these reasons, Syk is considered one of the most interesting biological targets of the last decade, as proved by the great number of papers and patents published, and the possibility of treating these pathologies by means of Syk kinase inhibitors has led to a great interest from the pharmaceutical and biotech industry. © 2010 Elsevier Ltd.
Imbimbo B.P.,Chiesi Farmaceutici |
Giardina G.A.M.,NiKem Research
Current Topics in Medicinal Chemistry | Year: 2011
According to the β-amyloid (Aβ) hypothesis, compounds that inhibit or modulate γ-secretase, the pivotal enzyme that generates Aβ, are potential therapeutics for Alzheimer's disease (AD). Studies in both transgenic and nontransgenic animal models of AD have indicated that γ-secretase inhibitors, administered by the oral route, are able to lower brain Aβ concentrations. However, scanty data are available on the effects of these compounds on brain Aβ deposition after chronic administration. Behavioral studies are also scarce with only one study indicating positive cognitive effects of a peptidomimetic compound acutely administered (DAPT). γ-Secretase inhibitors may cause abnormalities in the gastrointestinal tract, thymus, spleen and skin in experimental animals and in man. These toxic effects are likely due to inhibition of Notch cleavage, a transmembrane receptor involved in regulating cell-fate decisions. Some non-steroidal anti-inflammatory drugs (NSAIDs) and other small organic molecules have been found to modulate γ-secretase shifting its cleavage activity from longer to shorter β-amyloid species without affecting Notch cleavage. Long-term histopathological and behavioral animal studies are available with these NSAIDs (mainly ibuprofen) but it is unclear if the observed in vivo effects on Aβ brain pathology and learning depend on their activity on γ-secretase or on other biological targets. The most studied γ-secretase inhibitor, semagacestat (LY-450139), was shown to dose-dependently decrease the generation of Aβ in the cerebrospinal fluid of healthy humans. Unfortuantely, two large Phase 3 clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of the observation of detrimental effects on cognition and functionality in patients receiving the drug compared to those receiving placebo. These detrimental effects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of Aβ (the carboxy-terminal fragment of APP, or CTFβ) resulting from the block of the γ-secretase cleavage activity on APP. Two large Phase 3 studies in mild AD patients with tarenflurbil (R-flurbiprofen), a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notchsparing γ-secretase inhbitors and more potent, more brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks. © 2011 Bentham Science Publishers Ltd.
Colombo M.,NiKem Research |
Bianchi A.,Consorzio Interdisciplinare di Studi Biomolecolari ed Applicazioni Industriali CISI
Molecules | Year: 2010
In the last few years click chemistry reactions, and in particular coppercatalyzed cycloadditions, have been used intensively for the preparation of new bioconjugate molecules and materials applicable to biomedical and pharmaceutical areas. This review will be focused on conjugates of the tripeptide Arg-Gly-Asp formed by means of click chemistry reactions. This sequence is a well known binding motif for specific transmembrane proteins and is involved in cellular adhesion to the extracellular matrix, allowing the selective recognition of the biomolecule or polymer in which it is incorporated.
Fariello R.G.,Neurotune AG |
Ghelardini C.,University of Florence |
Di Cesare Mannelli L.,University of Florence |
Bonanno G.,University of Genoa |
And 4 more authors.
Neuropharmacology | Year: 2014
Dimiracetam, a bicyclic 2-pyrrolidinone derivative originally developed as cognition enhancer, is a member of the nootropic family for which anecdotal efficacy in models of neuropathic pain has been reported. Its antineuropathic activity was evaluated in established models of neuropathic pain induced by nerve injury, chemotherapy or MIA-induced osteoarthritis. Acutely, dimiracetam was very effective in models of antiretroviral drug induced painful neuropathy, oxaliplatin-induced hyperalgesia and in the MIA-osteoarthritis. Chronic dimiracetam dosing in the MIA and ART- induced models completely reverted hyperalgesia back to the level of healthy controls. Once reached, the maximal effect was maintained despite dose diminution and increased inter-dose interval. The effect of the last dose outlasted dimiracetam half-life longer than 12 times. In synaptosomal preparations, dimiracetam counteracted the NMDA-induced release of glutamate with highest potency in the spinal cord, possibly via NMDA receptor isoforms containing pH-sensitive GluN1 and GluN2A subunits. Dimiracetam appears to be a promising and safe treatment for neuropathic pain conditions for which there are very limited therapeutic options. © 2014 Elsevier Ltd. All rights reserved.
Villetti G.,Chiesi Farmaceutici SpA |
Pastore F.,Chiesi Farmaceutici SpA |
Bergamaschi M.,Chiesi Farmaceutici SpA |
Bassani F.,Chiesi Farmaceutici SpA |
And 20 more authors.
Journal of Pharmacology and Experimental Therapeutics | Year: 2010
The novel quaternary ammonium salt (3R)-3-[[[(3-fluorophenyl)[(3,4,5- trifluorophenyl)methyl]amino]carbonyl]oxy]-1-[2-oxo-2-(2-thienyl-)ethyl] -1-azoniabicyclo[2.2.2]octane bromide (CHF5407) showed subnanomolar affinities for human muscarinic M1 (hM1), M2 (hM2), and M3 (hM3) receptors and dissociated very slowly from hM3 receptors (t1/2 = 166 min) with a large part of the receptorial complex (54%) remaining undissociated at 32 h from radioligand washout. In contrast, [3H]CHF5407 dissociated quickly from hM2 receptors (t1/2 = 31 min), whereas [3H]tiotropium dissociated slowly from both hM3 (t1/2 = 163 min) and hM2 receptor (t1/2 = 297 min). In the guinea pig isolated trachea and human isolated bronchus, CHF5407 produced a potent (pIC50 = 9.0-9.6) and long-lasting (up to 24 h) inhibition of M3 receptor-mediated contractile responses to carbachol. In the guinea pig electrically driven left atrium, the M2 receptor-mediated inhibitory response to carbachol was recovered more quickly in CHF5407-pretreated than in tiotropium-pretreated preparations. CHF5407, administered intratracheally to anesthetized guinea pigs, potently inhibited acetylcholine (Ach)-induced bronchoconstriction with an ED50 value of 0.15 nmol/kg. The effect was sustained over a period of 24 h, with a residual 57% inhibition 48 h after antagonist administration at 1 nmol/kg. In conscious guinea pigs, inhaled CHF5407 inhibited Ach-induced bronchoconstriction for at least 24 h as did tiotropium at similar dosages. Cardiovascular parameters in anesthetized guinea pigs were not significantly changed by CHF5407, up to 100 nmol/kg i.v. and up to 1000 nmol/kg i.t. In conclusion, CHF5407 shows a prolonged antibronchospastic activity both in vitro and in vivo, caused by a very slow dissociation from M3 receptors. In contrast, CHF5407 is markedly short-acting at M2 receptors, a behavior not shared by tiotropium. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.
De Zani D.,NiKem Research |
Colombo M.,NiKem Research
Journal of Flow Chemistry | Year: 2012
O-Alkylation of phenol compounds was performed in a continuous flow apparatus under biphasic liquid/liquid conditions and promoted by tetrabutylammonium bromide (TBAB) as a phase-transfer catalyst. The segmented flow that is generated within the flow system is able to afford the desired ethers in high yield and in very short times. © 2012 Akadémiai Kiadó.
Colombo M.,NiKem Research |
Vallese S.,NiKem Research |
Peretto I.,NiKem Research |
Jacq X.,Hybrigenics |
And 3 more authors.
ChemMedChem | Year: 2010
High-throughput screening highlighted 9-oxo-9H-indeno[1,2-b]pyrazine-2,3- dicarbonitrile (1) as an active inhibitor of ubiquitin-specific proteases (USPs), a family of hydrolytic enzymes involved in the removal of ubiquitin from protein substrates. The chemical behavior of compound 1 was examined. Moreover, the synthesis and in vitro evaluation of new compounds, analogues of 1, led to the identification of potent and selective inhibitors of the deubiquitinating enzyme USP8. © 2010 Wiley-VCH Verlag GmbHand Co. KGaA, Weinheim.
van Schalkwyk D.A.,Australian National University |
Chan X.W.A.,Australian National University |
Misiano P.,NiKem Research |
Gagliardi S.,NiKem Research |
And 2 more authors.
Biochemical Pharmacology | Year: 2010
The V-type H+-ATPase is critical during the intraerythrocytic stage of the human malaria parasite Plasmodium falciparum. It is responsible for maintaining a near-neutral cytosolic pH (pH 7.3), an acidic digestive vacuole (pH 4.5-5.5) and the generation of an inside-negative plasma membrane potential (∼-95 mV). Inhibition of this pump is therefore likely to result in profound physiological disturbances within the parasite and parasite death, as illustrated previously by the antiplasmodial activity of the potent and specific inhibitors of the V-type H+-ATPase, bafilomycin A1 and concanamycin A. In this study we examined the antiplasmodial activity of a series of compounds previously designed, on the basis of the active structural constituents of bafilomycin A1, to inhibit the osteoclast V-type H+-ATPase. The compounds were tested against up to 4 strains of P. falciparum with varying chloroquine sensitivities. Of the 30 novel compounds tested, 9 had sub-micromolar antiplasmodial IC50 values, with the most active compound having an IC50 of 160 ± 20 nM. The activity of a number of these compounds was investigated in more detail. We show that these inhibitors acidify the parasite cytosol within seconds and that some inhibitors irreversibly kill the parasite within 0.5-4 h. The antiplasmodial activity of the V-type H+-ATPase inhibitors was strongly correlated with their ability to acidify the parasite cytosol (correlation coefficient 0.98). In combination studies, we show that the inhibitors act indifferently when combined with current antimalarials. Our data support the disruption of parasite pH regulation through inhibition of its V-type H+-ATPase as an antimalarial approach. © 2010 Elsevier Inc. All rights reserved.
PubMed | NiKem Research
Type: Journal Article | Journal: ChemMedChem | Year: 2010
High-throughput screening highlighted 9-oxo-9H-indeno[1,2-b]pyrazine-2,3-dicarbonitrile (1) as an active inhibitor of ubiquitin-specific proteases (USPs), a family of hydrolytic enzymes involved in the removal of ubiquitin from protein substrates. The chemical behavior of compound 1 was examined. Moreover, the synthesis and in vitro evaluation of new compounds, analogues of 1, led to the identification of potent and selective inhibitors of the deubiquitinating enzyme USP8.
PubMed | NiKem Research
Type: Journal Article | Journal: Molecules (Basel, Switzerland) | Year: 2010
In the last few years click chemistry reactions, and in particular copper-catalyzed cycloadditions, have been used intensively for the preparation of new bioconjugate molecules and materials applicable to biomedical and pharmaceutical areas. This review will be focused on conjugates of the tripeptide Arg-Gly-Asp formed by means of click chemistry reactions. This sequence is a well known binding motif for specific transmembrane proteins and is involved in cellular adhesion to the extracellular matrix, allowing the selective recognition of the biomolecule or polymer in which it is incorporated.