Aptuit Verona Srl

Verona, Italy

Aptuit Verona Srl

Verona, Italy
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Micheli F.,Aptuit Verona s.r.l.
ChemMedChem | Year: 2017

This Minireview describes a presentation made at the XXIV National Meeting in Medicinal Chemistry (NMMC) held in Perugia (Italy), September 11-14, 2016. It relates to the discovery of novel templates of the so-called "amino" region of dopamine D3 receptor antagonists. Moving from the early scaffolds, which were modified in the amine portion, this review discusses the variations that led to the discovery of new systems published in 2016, which allowed the identification of compounds endowed with great selectivity over the dopamine D2 receptor and the human ether-à-go-go-related gene (hERG) ion channel. The main efforts in characterizing these compounds were devoted not only to determining their potency and selectivity relative to closely associated targets (e.g., the dopamine D2 receptor), but to ensure a large therapeutic window versus liability points such as hERG. In particular, we present examples of derivatives with selectivities greater than 2000-fold. Furthermore, much focus is devoted to the overall developability of the scaffolds, ensuring that appropriate physicochemical and pharmacokinetic parameters are present in all compounds progressing through the screening cascade. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.


Michi M.,Aptuit Verona Srl | Breda M.,Aptuit Verona Srl | Belardi J.K.,Knopp Biosciences LLC | Dworetzky S.,Knopp Biosciences LLC | Solazzo L.,Aptuit Verona Srl
Bioanalysis | Year: 2017

Aim: Development of a high-sensitivity chiral LC-MS/MS method was required to evaluate a combination of pramipexole (S-PPX) and its enantiomer dexpramipexole (R-PPX) in a proposed clinical trial. The previously available methods suffered from low sensitivity for the (S)-enantiomer in the presence of the more abundant (R)- enantiomer. Based on the projected dosing regimen in the clinical trial, a 5000-fold improvement in sensitivity was required for the (S)-enantiomer. Methodology: Spiked human plasma samples were extracted by liquid-liquid extraction using ethyl acetate and injected onto a CHIRALPAK ID column under pH gradient conditions. Conclusion: An improved analytical method was developed and validated with a final LLQ for (S)-PPX of 0.1 ng/ml in the presence of 2000 ng/ml of (R)-PPX. © 2017 Future Science Ltd.


Micheli F.,Aptuit Verona s.r.l. | Heidbreder C.,Reckitt Benckiser
Expert Opinion on Therapeutic Patents | Year: 2013

Introduction: The synthesis and characterization of new highly potent and selective dopamine (DA) D3 receptor antagonists has permitted to characterize the role of the DA D3 receptor in the control of drug-seeking behavior and in the pathophysiology of impulse control disorders and schizophrenia. Areas covered: In the present review, the authors will first describe most recent classes of DA D3 receptor antagonists by reviewing about 43 patent applications during the 2007-2012 period; they will then outline the biological rationale in support of the use of selective DA D3 receptor antagonists in the treatment of drug addiction, impulse control disorders and schizophrenia. Expert opinion: The strongest clinical application and potential for selective DA D3 receptor antagonists lies in the reduction of drug-induced incentive motivation, the attenuation of drug's rewarding efficacy and the reduction in reinstatement of drug-seeking behavior triggered either by re-exposure to the drug itself, re-exposure to environmental cues that had been previously associated with drug-taking behavior or stress. The selectivity of these antagonists together with reduced lipophilicity (minimizing unspecific binding), increased brain penetration and improved physico-chemical profile are all key factors for clinical efficacy and safety. © Informa UK, Ltd.


Perdona E.,Glaxosmithkline | Perdona E.,Aptuit Verona S.r.l | Faggioni F.,Glaxosmithkline | Buson A.,Glaxosmithkline | And 3 more authors.
European Journal of Pharmacology | Year: 2011

A novel growth hormone secretagogues type 1a (GHS1a) receptors antagonist (2R)-N'-[3,5- bis(trifluoromethyl)phenyl]-2-[(8aR)-hexahydropyrrolo[1,2-a] pyrazin-2(1H)-yl]-2-(3- pyridinyl)ethanohydrazide (GSK1614343) was functionally characterised in rat pituitary adenoma cell line, RC-4B/C endogenously expressing GHS1a receptors. The antagonism profile of GSK1614343 was compared with that of 6-[(4-fluorophenyl)oxy]-2-methyl-3-{[(3S)-1-(1-methylethyl)-3- piperidinyl]methyl}-4(3H)-quinazolinone (YIL-781) another ghrelin receptor antagonist recently published. The activity of both compounds was also evaluated at rat recombinant GHS1a receptors. The characterization of the two antagonists was performed by intracellular calcium mobilization measurements by using fluorometric imaging plate reader (FLIPR) technology and inositol phosphate (IP) turnover measurements by [3H]-IP accumulation assay. RC-4B/C and U2-OS cells transiently transduced with rat GHS1a receptors virus were used. In RC-4B/C cells, GSK1614343 and YIL-781, depressed the ghrelin maximal response in FLIPR assay as result of hemi-equilibria phenomenon. When using the [3H]-IP accumulation assay both compounds behaved as competitive antagonist with pKB values of 8.03 for GSK1614343 and 7.54 for YIL-781. In rat recombinant receptor, GSK1614343 and YIL-781 inhibited the calcium response induced by ghrelin with pIC50 values of 7.90 and 8.27, respectively. GSK1614343 and YIL-781 did not show intrinsic activity in both endogenously expressed and recombinant rat GHS1a receptors. The new ghrelin receptor antagonist GSK1614343 is a potent competitive antagonist in rat pituitary RC-4B/C cells endogenously expressing GHS1a receptors when equilibrium conditions between ligand and receptor are reached in the test assay. GSK1614343 represents a useful tool to investigate the physiological relevance of the ghrelin system in rat models. © 2010 Elsevier B.V. All rights reserved.


Valko K.,Glaxosmithkline | Valko K.,Astex | Chiarparin E.,Aptuit Verona Srl | Nunhuck S.,Glaxosmithkline | And 2 more authors.
Journal of Pharmaceutical Sciences | Year: 2012

The concepts of drug efficiency (Deff) and Drug Efficiency Index (DEI) have been recently introduced as useful parameters to optimize the absorption, distribution, metabolism, elimination/excretion, and toxicity properties and in vivo efficacy potential of molecules during lead optimization and at pre-clinical stages. The available free drug concentration relative to dose depends on the compound's bioavailability, clearance, and the nonspecific binding to proteins and phospholipids. In this paper, we have demonstrated, using the data of over 115 known drug molecules, that the nonspecific binding can be determined in vitro very efficiently using biomimetic high-performance liquid chromatography measurements. DEI can therefore be estimated from in vitro measurements. The data show that high in vitro DEI values can be associated with lower efficacious dose. A strategy is described of how to use the DEI parameter during early lead optimization. An example is given to highlight the advantages of optimizing on DEI value rather than on potency alone. In order to facilitate the in silico compound design, correlation between in vitro DEI and in silico ligand efficiency parameters such as ligand lipophilicity efficiency has been revealed, suggesting the potential use of these efficiency-related parameters across lead optimization. © 2012 Wiley Periodicals, Inc.


Grant
Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2014-ETN | Award Amount: 2.79M | Year: 2015

Antimicrobial resistance is posing a continuously-rising threat to global health. Indeed, one key recommendation from the recent Action plan against the rising threats from Antimicrobial Resistance report (submitted by the Commission to the European Parliament and Council (15.11.2011)) is the development of effective antimicrobials or alternatives for treatment of human and animal infections. The INTEGRATE project is a direct response to this. We have assembled a team of 10 beneficiaries from eight EU member states, encompassing both academic and non-academic sectors and different disciplines, to form a consortium committed to training Early Stage Researchers (ESRs) in the discovery and preclinical validation of novel Gram-negative antibacterial agents and antibacterial targets. The principle aim of the consortium is to provide a training platform where students are exposed to every aspect of the antimicrobial discovery process, ranging from target identification and validation, through organic synthesis, in silico design and compound screening, to mode-of-action and possible resistance mechanisms. This exposure will be accomplished through a concrete secondment plan, coupled with a series of high-level consortium-wide training events and networking programmes. Our intention is to reverse the current fragmentation of approaches towards antibacterial discovery through mutual cooperation. The INTEGRATE training framework is built on an innovative research project aimed at targeting important but non-essential gene products as an effective means of reducing bacterial fitness, thereby facilitating clearance of the pathogen by the host immune system. To achieve this, the individual work programmes have been designed to seamlessly inter-mesh contributions from the fields of in silico design, organic synthesis, molecular biology and biochemistry, and the very latest in vitro and in vivo screening technologies.


Cervo L.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Di Clemente A.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Orru A.,Institute Of Translational Pharmacology Cnr | Moro F.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | And 5 more authors.
Addiction Biology | Year: 2013

Pharmacological stimulation of N-methyl-D-aspartate receptors (NMDAr) could enhance the outcome of cue-exposure therapy for smoking cessation. NMDAr stimulation can be achieved by increasing pharmacologically the synaptic levels of glycine, a necessary co-agonist. Here, we evaluate the effects of SSR504734, a selective inhibitor of glycine type I transporter (GlyT1) in an extinction-reinstatement procedure inducing robust and lasting nicotine-seeking behavior in rats. Male Wistar rats were trained to associate discriminative stimuli (SDs) with the availability of nicotine (0.03 mg/kg/65 μL/2 second/infusion) or sucrose (45-mg pellet) versus non-reward in two-lever operant cages. Reinforced response was followed by cue signaling 20-second time-out (CSs). Once the training criterion was met, rats underwent extinction of lever presses, in the absence of reinforcers, SDs and CSs. Re-exposure to nicotine or sucrose SD+/CS +, but not non-reward SD-/CS-, revived responding at the previously reinforced lever. Acute pre-treatment with SSR504734 (10 mg/kg i.p.) reduced nicotine-seeking but not sucrose-seeking behavior without influencing rats' locomotor activity. Sub-chronic treatment (10 mg/kg i.p. for 5 days) during daily exposure to SD +/CS+ reduced nicotine-seeking; however, this effect was transient, with return to SD+/CS+ responding at 72 hours. Full recovery to SD+/CS+ responding was observed after 1 month suggesting that SSR504734 sub-acute treatment did not engage the long-term plasticity mechanisms probably involved in nicotine-seeking. In conclusion, GlyT1-inhibitors might offer a therapeutic opportunity for acute cue-controlled nicotine-seeking, but the lack of persistent effects of the sub-chronic treatment associated with nicotine cues exposure suggests that short-term administration of GlyT1-inhibitor SSR504734 is not sufficient to promote extinction of nicotine-cue conditioned responding. © 2013 The Authors, Addiction Biology © 2013 Society for the Study of Addiction.


Grant
Agency: European Commission | Branch: H2020 | Program: MSCA-ITN-ETN | Phase: MSCA-ITN-2016 | Award Amount: 2.27M | Year: 2017

According to ECDC, over 4 million healthcare-associated infections in the EU cause 37,000 deaths and cost EUR 7 billion/year. Half of them are related to medical devices (i.e., catheters, implants) and 80% of these are related to bacterial biofilms. A recent EC report highlighted the medical device sectors role in driving EU economic growth, employing 500k people in 25k companies (80% are SMEs) with annual sales of EUR 85 billion. The strategy to prevent medical device-infections is alteration of the devices surface with antimicrobials. However, current antimicrobial surfaces dont control bacterial growth in tissue surrounding implants, and only Sterilex has received regulatory approval in the US as anti-biofilm agent. Participants in this proposal have earlier demonstrated a dramatic in vitro inhibition of biofilm formation by 3D-printing surfaces with antibiotics incorporated into the carrier polymers. This discovery opens new possibilities for printed medical devices that better resist biofilms. Our objective is to set-up a new European education platform to guide and inspire young researchers in the intersectoral exploration of innovative routes to counteract microbial biofilms by fabricating anti-infective, tailored, 3D-printed medical devices. Current opportunities for young researchers to receive an structured, inter-sectoral and up-to-date education on personalized medicine and medical devices are marginal, and to our knowledge PRINT-AID is the first ETN set up for this purpose. State-of-the-art printing technologies will be combined with in vitro and in vivo biofilm models and novel tools for data integration/standardization. Doctoral training will be performed within a high-quality network of 12 participants (5 industrial) from the EU and US. It will include online and face-to-face courses taught by researchers with academic and industrial expertise in biofilms, 3D-printing research, antimicrobials, material science, and drug development.


Dopamine (DA) D3 receptor antagonism might play a significant role in different therapeutic areas. A high number of preclinical studies on DA D3 receptor antagonists have shown efficacy in animal models of Parkinson's disease, schizophrenia and drug dependence. This Review covers the activities of medicinal chemists in this field over the last ten years towards the identification of truly selective compounds. Both primary and patent literature is reviewed here. Since the original discoveries, a clear trend towards the optimization of the developability properties of the new scaffold has clearly emerged with time, from both academic and industrial researchers. Examples of advanced leads from academia and industry are described. The latest potential therapeutic applications are reported too. Through the looking glass: A large number of dopamine D3receptor antagonist have shown efficacy in animal models of Parkinson's disease, schizophrenia and drug dependence. Medicinal chemistry research over the past decade aimed at the identification of selective compounds in this field, both in academia and in industry, is reviewed. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.


Dallow N.,Glaxosmithkline | Fina P.,Aptuit Verona Srl
Pharmaceutical Statistics | Year: 2011

In early drug development, especially when studying new mechanisms of action or in new disease areas, little is known about the targeted or anticipated treatment effect or variability estimates. Adaptive designs that allow for early stopping but also use interim data to adapt the sample size have been proposed as a practical way of dealing with these uncertainties. Predictive power and conditional power are two commonly mentioned techniques that allow predictions of what will happen at the end of the trial based on the interim data. Decisions about stopping or continuing the trial can then be based on these predictions. However, unless the user of these statistics has a deep understanding of their characteristics important pitfalls may be encountered, especially with the use of predictive power. The aim of this paper is to highlight these potential pitfalls. It is critical that statisticians understand the fundamental differences between predictive power and conditional power as they can have dramatic effects on decision making at the interim stage, especially if used to re-evaluate the sample size. The use of predictive power can lead to much larger sample sizes than either conditional power or standard sample size calculations. One crucial difference is that predictive power takes account of all uncertainty, parts of which are ignored by standard sample size calculations and conditional power. By comparing the characteristics of each of these statistics we highlight important characteristics of predictive power that experimenters need to be aware of when using this approach. © 2010 John Wiley & Sons, Ltd.

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