22 results on '"Ilaria Peretto"'
Search Results
2. Medicinal chemistry and therapeutic potential of muscarinic M3 antagonists
- Author
-
Bruno P. Imbimbo, Paola Petrillo, and Ilaria Peretto
- Subjects
Receptor, Muscarinic M3 ,Pharmacology ,medicine.medical_specialty ,Chemistry ,Chemistry, Pharmaceutical ,Muscarinic acetylcholine receptor M3 ,Muscarinic antagonist ,Muscarinic acetylcholine receptor M2 ,Muscarinic Antagonists ,Muscarinic acetylcholine receptor M1 ,Smooth muscle contraction ,Endocrinology ,Internal medicine ,Drug Discovery ,Muscarinic acetylcholine receptor ,Muscarinic acetylcholine receptor M4 ,medicine ,Humans ,Molecular Medicine ,Receptor ,medicine.drug - Abstract
Muscarinic acetylcholine receptors belong to the G-protein-coupled receptors family. Currently five different receptor subtypes have been identified and cloned. M3 receptor subtypes are coupled to G(q) family proteins and increase phosphatidyl inositol hydrolysis and calcium release from internal stores. They are widely distributed both in the central nervous system and in the periphery. At the central level, M3 receptor subtypes are involved in modulation of neurotransmitter release, temperature homeostasis, and food intake, while in the periphery they induce smooth muscle contraction, gland secretion, indirect relaxation of vascular smooth muscle, and miosis. The main therapeutic applications of M3 antagonists include overactive bladder (OAB), chronic obstructive pulmonary disease (COPD), and pain-predominant irritable bowel syndrome (IBS). The introduction of selective M3 antagonists has not improved clinical efficacy compared with the old non-selective antimuscarinics but has reduced the rate of adverse events mediated by the blockade of cardiac M2 receptors (tachycardia) and central M1 receptors (cognitive impairment). Improved tolerability has been obtained also with controlled release or with inhaled formulations. However, there is still a need for safer M3 antagonists for the treatment of COPD and better-tolerated and more effective compounds for the therapy of OAB. New selective muscarinic M3 antagonists currently in early discovery and under development have been designed to address these issues. However, as M3 receptors are widely located in various tissues including salivary glands, gut smooth muscles, iris, and ciliary muscles, further clinical improvements may derive from the discovery and the development of new compounds with tissue rather than muscarinic receptor subtype selectivity.
- Published
- 2009
3. Speeding Up Discovery Chemistry: New Perspectives in Medicinal Chemistry
- Author
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Matteo Colombo and Ilaria Peretto
- Subjects
Chemistry ,Drug discovery ,Organic chemistry ,Chemistry (relationship) ,Flow chemistry ,Medicinal chemistry - Published
- 2009
4. Simple microwave-assisted ligand-free suzuki cross-coupling: Functionalization of halo-pyrimidine moieties
- Author
-
Matteo Colombo, Marco Giglio, and Ilaria Peretto
- Subjects
Coupling ,chemistry.chemical_compound ,Pyrimidine ,chemistry ,Ligand ,Organic Chemistry ,Microwave irradiation ,Surface modification ,Combinatorial chemistry ,Microwave assisted - Abstract
An advantageous ligand-free protocol for Suzuki couplings is described. The synthetic procedure entails microwave irradiation for the reduction of the reaction times and the use of silica cartridges for the purification. Dihalo-pyrimidine structures, interesting scaffolds in medicinal chemistry, were chosen as test compounds.
- Published
- 2008
5. γ-Secretase Modulation and its Promise for Alzheimers Disease: a Medicinal Chemistry Perspective
- Author
-
Elena La Porta and Ilaria Peretto
- Subjects
chemistry.chemical_classification ,Protease ,biology ,business.industry ,medicine.medical_treatment ,Peptide ,General Medicine ,Disease ,Pharmacology ,medicine.disease ,chemistry ,Drug Discovery ,medicine ,biology.protein ,Structure–activity relationship ,Pharmacophore ,Alzheimer's disease ,business ,Amyloid precursor protein secretase ,Gamma secretase - Abstract
Gamma-secretase modulation holds the promise for the development of a disease-modifying therapy for Alzheimer's disease (AD). This novel concept of manipulating the cleavage specificity of the gamma secretase enzyme by pharmacological means implies that steady state levels of the potentially disease-causing amyloid-beta(1-42) peptide can be lowered without the undesired side effects associated with full inhibition of this aspartyl-type protease. Following on from the initial discovery that certain non-steroidal anti-inflammatory drugs (NSAIDs) exhibit properties characteristic of gamma secretase modulators, this class of compounds has been extensively studied and exploited, leading to the discovery of NSAIDs derivatives endowed with improved potency for the reduction of amyloid-beta(1-42) peptide production. In addition, a very limited number of non-NSAID derived gamma secretase modulators has also been recently claimed in the patent literature, suggesting that only a restricted number of pharmacophores might be involved in the modulation of gamma-secretase.
- Published
- 2008
6. Novel class of benzoic acid ester derivatives as potent PDE4 inhibitors for inhaled administration in the treatment of respiratory diseases
- Author
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Elena La Porta, Fabrizio Facchinetti, Maurizio Delcanale, Paola Puccini, Matilde Guala, Silvia Capacchi, Elisabetta Armani, Francesco Amadei, Paola Caruso, Nadia Moretto, Laura Carzaniga, Eleonora Ghidini, Franco Bassani, Maurizio Civelli, Fanti Renato De, Carmelida Capaldi, Roberta Volta, Gabriele Amari, Gino Villetti, Andrea Rizzi, Riccardo Patacchini, Ilaria Peretto, Valentina Cenacchi, Silvia Catinella, Chiara Carnini, and Pier Tonino Bolzoni
- Subjects
Drug ,Ovalbumin ,Protein Conformation ,media_common.quotation_subject ,Guinea Pigs ,Pharmacology ,Crystallography, X-Ray ,Benzoates ,Cell Line ,chemistry.chemical_compound ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Administration, Inhalation ,Eosinophilia ,medicine ,para-Aminobenzoates ,Animals ,Humans ,Lung Diseases, Obstructive ,Respiratory system ,Lung ,media_common ,Asthma ,ADME ,Benzoic acid ,Sulfonamides ,Ethanol ,Anti-Inflammatory Agents, Non-Steroidal ,Esters ,Stereoisomerism ,medicine.disease ,In vitro ,Rats ,Molecular Docking Simulation ,chemistry ,Chronic Disease ,Leukocytes, Mononuclear ,Molecular Medicine ,Phosphodiesterase 4 Inhibitors - Abstract
The first steps in the selection process of a new anti-inflammatory drug for the inhaled treatment of asthma and chronic obstructive pulmonary disease are herein described. A series of novel ester derivatives of 1-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(3,5-dichloropyridin-4-yl) ethanol have been synthesized and evaluated for inhibitory activity toward cAMP-specific phosphodiesterase-4 (PDE4). In particular, esters of variously substituted benzoic acids were extensively explored, and structural modification of the alcoholic and benzoic moieties were performed to maximize the inhibitory potency. Several compounds with high activity in cell-free and cell-based assays were obtained. Through the evaluation of opportune in vitro ADME properties, a potential candidate suitable for inhaled administration in respiratory diseases was identified and tested in an in vivo model of pulmonary inflammation, proving its efficacy.
- Published
- 2014
7. Lead generation and lead optimisation approaches in the discovery of selective, non-peptide ORL-1 receptor agonists and antagonists
- Author
-
Silvano Ronzoni, Giuseppe Am Giardina, and Ilaria Peretto
- Subjects
Pharmacology ,Research groups ,medicine.drug_class ,Chemistry ,General Medicine ,Non peptide ,Nociceptin receptor ,Opioid receptor ,Drug Discovery ,Orphanin FQ ,Lofentanil ,medicine ,Receptor ,Endogenous agonist ,medicine.drug - Abstract
The discovery of the opioid receptor like-1 (ORL-1) receptor and of its endogenous agonist nociceptin/orphanin FQ has attracted great interest in the scientific community giving rise, in the last five years, to a flurry of biological studies aimed at elucidating the role of this new receptor. Hence, the involvement of the ORL-1 receptor in many important processes, such as antinociception, learning and memory, feeding and anxiety, has been well documented. However, a clear understanding of the potential therapeutic value associated with the modulation of the ORL-1 receptor needs the development of selective non-peptide agonists and antagonists allowing systemic routes of administration. This review addresses the advances made by several research groups in the discovery of such compounds and discusses the medicinal chemistry strategies which, starting from the first non-selective ligands NalBzoH and lofentanil, led to the disclosure of highly potent and selective agonists and antagonists, such as Ro 64-619...
- Published
- 2001
8. ChemInform Abstract: Medicinal Chemistry and Therapeutic Potential of Muscarinic M3 Antagonists
- Author
-
Bruno P. Imbimbo, Paola Petrillo, and Ilaria Peretto
- Subjects
Vascular smooth muscle ,Temperature homeostasis ,Chemistry ,Muscarinic acetylcholine receptor ,Muscarinic acetylcholine receptor M3 ,Muscarinic acetylcholine receptor M2 ,General Medicine ,Muscarinic acetylcholine receptor M1 ,Smooth muscle contraction ,Pharmacology ,Receptor - Abstract
Muscarinic acetylcholine receptors belong to the G-protein-coupled receptors family. Currently five different receptor subtypes have been identified and cloned. M3 receptor subtypes are coupled to Gq family proteins and increase phosphatidyl inositol hydrolysis and calcium release from internal stores. They are widely distributed both in the central nervous system and in the periphery. At the central level, M3 receptor subtypes are involved in modulation of neurotransmitters release, temperature homeostasis, food intake, while in the periphery they induce smooth muscle contraction, gland secretion, indirect relaxation of vascular smooth muscle, and miosis. The main therapeutic applications of M3 antagonists include overactive bladder (OAB), chronic obstructive pulmonary disease (COPD), and pain-predominant irritable bowel syndrome (IBS). The introduction of selective M3 antagonists has not improved clinical efficacy compared with the old non-selective antimuscarinics but has reduced the rate of adverse events mediated by the blockade of cardiac M2 receptors (tachy- cardia) and central M1 receptors (cognitive impairment). Improved tolerability has been obtained also with controlled release or with inhaled formulations. However, there is still a need for safer M3 antagonists for the treatment of COPD and better-tolerated and more effective compounds for the therapy of OAB. New selective muscarinic M3 antagonists currently in early discovery and under development have been designed to address these issues. However, as M3 receptors are widely located in various tissues including salivary glands, gut smooth muscles, iris, and ciliary muscles, further clinical improvements may derive from the discovery and the development of new compounds with tissue rather
- Published
- 2010
9. Semagacestat, a gamma-secretase inhibitor for the potential treatment of Alzheimer's disease
- Author
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Bruno P, Imbimbo and Ilaria, Peretto
- Subjects
Patents as Topic ,Clinical Trials as Topic ,Structure-Activity Relationship ,Alanine ,Molecular Structure ,Alzheimer Disease ,Animals ,Humans ,Azepines ,Drugs, Investigational ,Amyloid Precursor Protein Secretases - Abstract
Eli LillyCo is developing semagacestat, an inhibitor of the gamma-secretase enzyme. This enzyme is pivotal in the generation of beta-amyloid (A beta), a neurotoxic endogenous peptide believed to be involved in the pathogenesis of Alzheimer's disease (AD). In animals, semagacestat reduced A beta levels in the plasma, CSF and brain; however, studies have not reported on cognitive effect of this compound. Phase I clinical trials in healthy volunteers have evaluated doses ranging from 5 to 140 mg/day and phase II trials in patients with AD have evaluated doses ranging from 30 to 140 mg/day for up to 14 weeks. Trials in both healthy volunteers and patients with AD have demonstrated a dose-dependent inhibition of plasma A beta levels, and a recent trial in healthy volunteers demonstrated a robust, dose-dependent inhibition of newly generated A beta in the CSF after single oral doses. The main adverse events involved the gastrointestinal tract. In 2008, two large phase III clinical trials in patients with mild-to-moderate AD were initiated by Eli Lilly. Semagacestat is the most advanced gamma-secretase inhibitor and represents a major hope among therapies designed to slow the rate of cognitive decline of patients with AD.
- Published
- 2009
10. ChemInform Abstract: Simple Microwave-Assisted Ligand-Free Suzuki Cross-Coupling: Functionalization of Halo-pyrimidine Moieties
- Author
-
Matteo Colombo, Ilaria Peretto, and Marco Giglio
- Subjects
Coupling ,chemistry.chemical_compound ,Pyrimidine ,chemistry ,Ligand ,Microwave irradiation ,Organic chemistry ,Surface modification ,General Medicine ,Combinatorial chemistry ,Microwave assisted - Abstract
An advantageous ligand-free protocol for Suzuki couplings is described. The synthetic procedure entails microwave irradiation for the reduction of the reaction times and the use of silica cartridges for the purification. Dihalo-pyrimidine structures, interesting scaffolds in medicinal chemistry, were chosen as test compounds.
- Published
- 2008
11. Gamma-secretase modulation and its promise for Alzheimer's disease: a medicinal chemistry perspective
- Author
-
Ilaria, Peretto and Elena, La Porta
- Subjects
Structure-Activity Relationship ,Alzheimer Disease ,Anti-Inflammatory Agents, Non-Steroidal ,Animals ,Humans ,Amyloid Precursor Protein Secretases ,Enzyme Inhibitors - Abstract
Gamma-secretase modulation holds the promise for the development of a disease-modifying therapy for Alzheimer's disease (AD). This novel concept of manipulating the cleavage specificity of the gamma secretase enzyme by pharmacological means implies that steady state levels of the potentially disease-causing amyloid-beta(1-42) peptide can be lowered without the undesired side effects associated with full inhibition of this aspartyl-type protease. Following on from the initial discovery that certain non-steroidal anti-inflammatory drugs (NSAIDs) exhibit properties characteristic of gamma secretase modulators, this class of compounds has been extensively studied and exploited, leading to the discovery of NSAIDs derivatives endowed with improved potency for the reduction of amyloid-beta(1-42) peptide production. In addition, a very limited number of non-NSAID derived gamma secretase modulators has also been recently claimed in the patent literature, suggesting that only a restricted number of pharmacophores might be involved in the modulation of gamma-secretase.
- Published
- 2008
12. Chemistry strategies in early drug discovery: an overview of recent trends
- Author
-
Ilaria Peretto and Matteo Colombo
- Subjects
Pharmacology ,Drug Industry ,Chemistry ,Drug discovery ,Research ,Nanotechnology ,Flow chemistry ,Business process discovery ,chemistry.chemical_compound ,Pharmaceutical Preparations ,Drug Discovery ,Click chemistry ,High activity ,Drug Evaluation ,Technology, Pharmaceutical ,Organic synthesis ,Chemistry (relationship) ,Biochemical engineering - Abstract
In the scenario of a continuous request for better drugs in shorter times, medicinal chemists must face the challenging task of preparing new patentable molecules, combining high activity and selectivity, drug-likeness and good pharmacokinetic properties. Multiparametric optimization requires a substantial improvement of the efficacy and throughput of the early discovery process, leading to a significant revolution in organic synthesis and chemistry technologies. Chemists are searching for ways to simplify synthetic protocols, for example, by the use of polymer-assisted solution-phase synthesis, microwave-assisted organic synthesis and flow chemistry. Organic synthesis is benefiting of fast and robust reactions, with breakthrough approaches often entailing the privileged use of multicomponent reactions, click chemistry and ring-closing metathesis.
- Published
- 2007
13. Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 1)
- Author
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Giulio Dondio, Marco Bergamaschi, Roberta Scudellaro, Andrea Rizzi, Ilaria Peretto, and Andrés G. Fernández, Roberto Forlani, P. Petrillo, Chiara Bigogno, Bruno P. Imbimbo, Gino Villetti, Elisabetta Armani, Giuseppe Giardina, Elena La Porta, Enza Santoro, Maurizio Delcanale, Paola Misiano, Luigi Radice, Riccardo Patacchini, Alessandra Giardini, Luca F. Raveglia, Francesca Scarpitta, Maurizio Civelli, Claudia Fossati, Matilde Guala, Stefano Radaelli, Carolina Salcedo, and Gabriele Amari
- Subjects
Male ,Models, Molecular ,Cell Membrane Permeability ,Tertiary amine ,Stereochemistry ,Urinary Bladder ,Administration, Oral ,CHO Cells ,In Vitro Techniques ,Imidazolidines ,Chemical synthesis ,Mice ,Radioligand Assay ,Structure-Activity Relationship ,Cricetulus ,Cricetinae ,Microsomes ,Drug Discovery ,Muscarinic acetylcholine receptor ,Functional selectivity ,Animals ,Humans ,Receptor, Muscarinic M3 ,Receptor, Muscarinic M2 ,Chemistry ,Muscarinic acetylcholine receptor M3 ,Biological activity ,Muscarinic acetylcholine receptor M2 ,Muscle, Smooth ,Atrial Function ,Rats ,Molecular Medicine ,Female ,Pharmacophore ,Caco-2 Cells ,Muscle Contraction - Abstract
Pharmacophore-based structural identification, synthesis, and structure -activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50 showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki ) 4.8 nM and for M2 receptor Ki ) 1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor.
- Published
- 2007
14. Discovery of diaryl imidazolidin-2-one derivatives, a novel class of muscarinic M3 selective antagonists (Part 2)
- Author
-
Sergio Menegon, Gabriele Amari, Bruno P. Imbimbo, Elisabetta Armani, Giulio Dondio, Luigi Radice, Elena La Porta, Maurizio Delcanale, Marco Bergamaschi, Alessandra Giardini, Paola Petrillo, Luca F. Raveglia, Francesca Scarpitta, Maurizio Civelli, Claudia Fossati, Giuseppe Giardina, Roberta Scudellaro, Andrea Rizzi, Enza Santoro, Gino Villetti, Stefano Radaelli, Riccardo Patacchini, Matilde Guala, Alberto Cerri, Franco Bassani, and Ilaria Peretto
- Subjects
Male ,Stereochemistry ,Bronchoconstriction ,Guinea Pigs ,CHO Cells ,In Vitro Techniques ,Imidazolidines ,Guinea pig ,Radioligand Assay ,Structure-Activity Relationship ,Cricetulus ,In vivo ,Cricetinae ,Drug Discovery ,Muscarinic acetylcholine receptor ,Functional selectivity ,Animals ,Humans ,Acetylcholine receptor ,Receptor, Muscarinic M3 ,Chemistry ,Muscarinic acetylcholine receptor M3 ,Biological activity ,Muscarinic acetylcholine receptor M2 ,Muscle, Smooth ,Myocardial Contraction ,Bronchodilator Agents ,Quaternary Ammonium Compounds ,Trachea ,Molecular Medicine ,Muscle Contraction - Abstract
Synthesis and biological activity of a novel class of quaternary ammonium salt muscarinic M3 receptor antagonists, showing high selectivity versus the M2 receptor, are described. Selected compounds exhibited potent anticholinergic properties, in isolated guinea-pig trachea, and good functional selectivity for trachea over atria. In vivo, the same compounds potently inhibited acetylcholine-induced bronchoconstriction after intratracheal administration in the guinea pig.
- Published
- 2007
15. Solution phase synthesis of a library of tetrasubstituted pyrrole amides
- Author
-
Nickolas Regalia, and Maurizio Taddei, Ivana Bianchi, Roberto Forlani, Raveglia Luca Francesco, Giacomo Minetto, and Ilaria Peretto
- Subjects
Molecular Structure ,Chemistry ,General Chemistry ,General Medicine ,Combinatorial chemistry ,Amides ,Chemical space ,Pyrrole derivatives ,chemistry.chemical_compound ,Automation ,Aminolysis ,Models, Chemical ,Pharmaceutical Preparations ,Cyclization ,Organic chemistry ,Combinatorial Chemistry Techniques ,Pyrroles ,Microwaves ,Solution phase synthesis ,Pyrrole - Abstract
An efficient strategy for the solution-phase parallel synthesis of a library of pyrrole-amides is described. Key reactions include functional homologation of beta-ketoesters with a set of aldehydes followed by oxidation to produce a series of differently substituted 1,4-dicarbonyl compounds. Rapid cyclization using a microwave-assisted Paal-Knorr reaction provided a set of 24 pyrrole esters that were further functionalized through a trimethylaluminum-mediated aminolysis to obtain a larger library of 288 diverse pyrrole-3-amides. The tetrasubstitution allows a good exploration of the chemical space around the central pyrrole core. The last step was entirely automated with a Bohdan Myriad personal synthesizer.
- Published
- 2006
16. Synthesis and biological activity of flurbiprofen analogues as selective inhibitors of beta-amyloid(1)(-)(42) secretion
- Author
-
Ilaria Peretto, Michele Zandi, Benedetta Riccardi, Pier Tonino Bolzoni, Paola Caruso, Silvia Marchetti, Elda Del Giudice, Nadia Moretto, Paola Puccini, Bruno P. Imbimbo, Carlo Parini, Paola Misiano, Andrea Rizzi, Chiara Bigogno, Ivano Rondelli, Marcello Biscaioli, Giulio Dondio, Silvia Catinella, Fabrizio Facchinetti, Laura Fontanella, Luca F. Raveglia, Gino Villetti, Valentina Cenacchi, and Stefano Radaelli
- Subjects
medicine.medical_specialty ,Cell Membrane Permeability ,Flurbiprofen ,Administration, Oral ,Mice, Transgenic ,In Vitro Techniques ,Mice ,Structure-Activity Relationship ,Pharmacokinetics ,Oral administration ,Alzheimer Disease ,Internal medicine ,Cell Line, Tumor ,Drug Discovery ,medicine ,Structure–activity relationship ,Animals ,Humans ,Cyclooxygenase Inhibitors ,ADME ,Immunoassay ,Amyloid beta-Peptides ,biology ,Chemistry ,Anti-Inflammatory Agents, Non-Steroidal ,Biological activity ,Stereoisomerism ,Glioma ,Peptide Fragments ,Rats ,Endocrinology ,Enzyme inhibitor ,Blood-Brain Barrier ,Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ,Injections, Intravenous ,biology.protein ,Molecular Medicine ,Cyclooxygenase ,Caco-2 Cells ,medicine.drug - Abstract
Flurbiprofen, a nonsteroidal antiinflammatory drug (NSAID), has been recently described to selectively inhibit beta-amyloid(1)(-)(42) (Abeta42) secretion, the most toxic component of the senile plaques present in the brain of Alzheimer patients. The use of this NSAID in Alzheimer's disease (AD) is hampered by a significant gastrointestinal toxicity associated with cyclooxygenase (COX) inhibition. New flurbiprofen analogues were synthesized, with the aim of increasing Abeta42 inhibitory potency while removing anti-COX activity. In vitro ADME developability parameters were taken into account in order to identify optimized compounds at an early stage of the project. Appropriate substitution patterns at the alpha position of flurbiprofen allowed for the complete removal of anti-COX activity, while modifications at the terminal phenyl ring resulted in increased inhibitory potency on Abeta42 secretion. In rats, some of the compounds appeared to be well absorbed after oral administration and to penetrate into the central nervous system. Studies in a transgenic mice model of AD showed that selected compounds significantly decreased plasma Abeta42 concentrations. These new flurbiprofen analogues represent potential drug candidates to be developed for the treatment of AD.
- Published
- 2005
17. Cell penetrable peptoid carrier vehicles: synthesis and evaluation
- Author
-
Ilaria, Peretto, Rosario M, Sanchez-Martin, Xui-hong, Wang, John, Ellard, Stifun, Mittoo, and Mark, Bradley
- Subjects
Mice ,Peptoids ,Models, Chemical ,Molecular Structure ,Cell Line, Tumor ,Animals ,Humans ,Carrier Proteins ,Flow Cytometry ,Fluoresceins ,Cell Line - Abstract
Using a highly efficient solid-phase route a series of fluorescein conjugated peptoid oligomers were synthesised and observed to display remarkable cell penetrating properties, offering the possibility of highly efficient cellular targeting.
- Published
- 2003
18. A new synthetic approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one(J-113397), the first non-peptide ORL-1 receptor antagonist
- Author
-
Ilaria Peretto, Gian Piero Pollini, Silvano Ronzoni, Giuseppe Giardina, Claudio Trapella, and Carmela De Risi
- Subjects
Bicyclic molecule ,Chemistry ,Stereochemistry ,Narcotic Antagonists ,Spectrum Analysis ,Organic Chemistry ,Clinical Biochemistry ,Substituent ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,Nociceptin Receptor ,Adduct ,chemistry.chemical_compound ,Piperidines ,Drug Discovery ,Receptors, Opioid ,Molecular Medicine ,Hydroxymethyl ,Benzimidazoles ,Piperidine ,Enantiomer ,Methyl acrylate ,Molecular Biology ,Chromatography, High Pressure Liquid - Abstract
An efficient approach to 1-[(3R,4R)-1-cyclooctylmethyl-3-hydroxymethyl-4-piperidyl]-3-ethyl-1,3-dihydro-benzimidazol-2-one (J-113397) 1, the first non-peptide ORL-1 receptor antagonist described in literature, is outlined. After construction of the piperidine framework through Dieckmann cyclization of the Michael adduct 8 of cyclooctylmethylamine to methyl acrylate, condensation with o-phenylendiamine produced the beta-enamino ester 2, which has been conveniently used to construct the benzimidazolone substituent at C-4. Catalytic hydrogenation of intermediate 11 followed by base-promoted cis--trans isomerization of the key compound 12 led to the formation of ester 13, which was converted to the racemic title compound by LiAlH(4) reduction. The pure enantiomers were obtained by chiral preparative HPLC separation using a derivatized cellulose-based stationary phase.
- Published
- 2001
19. O3-06-05 New flurbiprofen analogues, devoid of cyclooxygenase activity, selectively lower β-amyloid1–42 secretion
- Author
-
Ilaria Peretto, Benedetta Riccardi, Silvia Marchetti, Paola Puccini, Bruno P. Imbimbo, Silvia Ghirardi, Gino Villetti, Carlo Parini, Roberta Volta, Silvia Catinella, Stefano Radaelli, Raveglia Luca Francesco, Ivano Rondelli, and Andrea Rizzi
- Subjects
Aging ,biology ,Chemistry ,General Neuroscience ,Flurbiprofen ,Pharmacology ,biology.protein ,medicine ,Secretion ,Neurology (clinical) ,Cyclooxygenase ,Geriatrics and Gerontology ,Developmental Biology ,medicine.drug - Published
- 2004
20. Cell penetrable peptoid carrier vehicles: synthesis and evaluationElectronic supplementary information (ESI) available: experimental details. See http://www.rsc.org/suppdata/cc/b3/b306438g
- Author
-
Rosario M. Sánchez-Martín, Ilaria Peretto, Mark Bradley, Stifun Mittoo, Xui-hong Wang, and John M. Ellard
- Subjects
Chemistry ,Cell ,Metals and Alloys ,Peptoid ,Nanotechnology ,General Chemistry ,Cellular targeting ,Conjugated system ,Combinatorial chemistry ,Catalysis ,Surfaces, Coatings and Films ,Electronic, Optical and Magnetic Materials ,chemistry.chemical_compound ,medicine.anatomical_structure ,Materials Chemistry ,Ceramics and Composites ,medicine ,Fluorescein - Abstract
Using a highly efficient solid-phase route a series of fluorescein conjugated peptoid oligomers were synthesised and observed to display remarkable cell penetrating properties, offering the possibility of highly efficient cellular targeting.
- Published
- 2003
21. Discovery of Diaryl Imidazolidin-2-one Derivatives, a Novel Class of Muscarinic M3 Selective Antagonists (Part 2).
- Author
-
Ilaria Peretto, Claudia Fossati, Giuseppe A. M. Giardina, Alessandra Giardini, Matilde Guala, Elena La Porta, Paola Petrillo, Stefano Radaelli, Luigi Radice, Luca F. Raveglia, Enza Santoro, Roberta Scudellaro, Francesca Scarpitta, Alberto Cerri, Sergio Menegon, Giulio M. Dondio, Andrea Rizzi, Elisabetta Armani, Gabriele Amari, and Maurizio Civelli
- Subjects
- *
AMMONIUM salts , *MUSCARINIC receptors , *PARASYMPATHOLYTIC agents , *BRONCHOCONSTRICTOR agents - Abstract
Synthesis and biological activity of a novel class of quaternary ammonium salt muscarinic M3 receptor antagonists, showing high selectivity versus the M2 receptor, are described. Selected compounds exhibited potent anticholinergic properties, in isolated guinea-pig trachea, and good functional selectivity for trachea over atria. In vivo, the same compounds potently inhibited acetylcholine-induced bronchoconstriction after intratracheal administration in the guinea pig. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
22. Discovery of Diaryl Imidazolidin-2-one Derivatives, a Novel Class of Muscarinic M3 Selective Antagonists (Part 1).
- Author
-
Ilaria Peretto, Roberto Forlani, Claudia Fossati, Giuseppe A. M. Giardina, Alessandra Giardini, Matilde Guala, Elena La Porta, Paola Petrillo, Stefano Radaelli, Luigi Radice, Luca F. Raveglia, Enza Santoro, Roberta Scudellaro, Francesca Scarpitta, Chiara Bigogno, Paola Misiano, Giulio M. Dondio, Andrea Rizzi, Elisabetta Armani, and Gabriele Amari
- Subjects
- *
MUSCARINIC receptors , *RESPIRATORY diseases , *QUATERNARY ammonium salts , *AMINES - Abstract
Pharmacophore-based structural identification, synthesis, and structure−activity relationships of a new class of muscarinic M3 receptor antagonists, the diaryl imidazolidin-2-one derivatives, are described. The versatility of the discovered scaffold allowed for several structural modifications that resulted in the discovery of two distinct classes of compounds, specifically a class of tertiary amine derivatives (potentially useful for the treatment of overactive bladder by oral administration) and a class of quaternary ammonium salt derivatives (potentially useful for the treatment of respiratory diseases by the inhalation route of administration). In this paper, we describe the synthesis and biological activity of tertiary amine derivatives. For these compounds, selectivity for the M3 receptor toward the M2 receptor was crucial, because the M2 receptor subtype is mainly responsible for adverse systemic side effects of currently marketed muscarinic antagonists. Compound 50showed the highest selectivity versus M2 receptor, with binding affinity for M3 receptor Ki4.8 nM and for M2 receptor Ki1141 nM. Functional in vitro studies on selected compounds confirmed the antagonist activity toward the M3 receptor and functional selectivity toward the M2 receptor. [ABSTRACT FROM AUTHOR]
- Published
- 2007
- Full Text
- View/download PDF
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