Publications (22)44.04 Total impact
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Article: Discovery and biological characterization of (2R,4S)-1'-acetyl-N-{(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}-2-(4-fluoro-2-methylphenyl)-N-methyl-4,4'-bipiperidine-1-carboxamide as a new potent and selective neurokinin 1 (NK1) receptor antagonist clinical candidate.
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ABSTRACT: A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK(1) receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK(1) receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK(1) receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.Journal of Medicinal Chemistry 02/2011; 54(4):1071-9. · 4.80 Impact Factor -
Article: NMR spectroscopy and surface tension measurements applied to the study of self-association of casopitant mesylate, a novel NK1 antagonist.
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ABSTRACT: The aggregation behaviour of casopitant mesylate, a new NK1 antagonist drug, was investigated by means of NMR spectroscopy and surface tension measurements. The critical micelle concentration (CMC) in glycine buffer at pH 3.5 was determined by analyzing the (1)H NMR chemical shifts variation and the surface tension in function of the concentration in a series of solutions. The temperature dependence of the CMC was also evaluated by NMR spectroscopy as well as the thermodynamic parameters contributing to the aggregation discussed. Surface tension measurements were conducted as well in the formulation conditions, e.g. in the presence of sodium chloride.Journal of pharmaceutical and biomedical analysis 01/2011; 54(1):48-52. · 2.45 Impact Factor -
Article: Detection, identification and quantification of a new de-fluorinated impurity in casopitant mesylate drug substance during late phase development: an analytical challenge involving a multidisciplinary approach.
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ABSTRACT: During late phase development of the selective NK1 receptor antagonist casopitant mesylate, a de-fluorinated impurity was discovered and quantified by an orthogonal analytical approach, using NMR and LC-MS. A dedicated (19)F NMR method was initially developed for first line identification and semi-quantification of the impurity. Subsequently, a more accurate quantification was achieved by means of a selective normal-phase LC-MS method, which was fully validated. The results obtained on the development batches of the drug substance were used by the project team to set up a suitable control strategy and ultimately to ensure patient safety and the progression of the project.Journal of pharmaceutical and biomedical analysis 01/2011; 54(1):67-73. · 2.45 Impact Factor -
Article: Application of LC-NMR and HR-NMR to the characterization of biphenyl impurities in the synthetic route development for vestipitant, a novel NK1 antagonist.
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ABSTRACT: Vestipitant (1) is a novel NK1 antagonist currently under investigation for the treatment of CNS disorders and emesis. The first synthetic step comprised a Grignard synthesis. An impurity was identified and initially expected to be a symmetric biphenyl. This paper reports the work to synthesise the supposed structure and the spectroscopic analyses (LC-NMR and HR-NMR) to correctly identify the real structure and understand the chemical pathway of the impurity.Journal of pharmaceutical and biomedical analysis 11/2010; 53(3):389-95. · 2.45 Impact Factor -
Article: A multi-technique approach using LC-NMR, LC-MS, semi-preparative HPLC, HR-NMR and HR-MS for the isolation and characterization of low-level unknown impurities in GW876008, a novel corticotropin-release factor 1 antagonist.
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ABSTRACT: A multi-technique approach was applied in order to fully characterize four low-level unknown impurities of GW876008, a novel CRF(1) receptor antagonist. Liquid chromatography (LC)-NMR spectroscopy was used in combination with LC-MS to obtain detailed information regarding the structure of the two major impurities present in batches of GW876008 and observed in the first synthetic scale-up for preclinical use. Two additional impurities were unexpectedly found at greater levels in a large scale synthesis for clinical use and their structure was elucidated by means of high resolution (HR)-MS and HR-NMR, after a small scale preparative HPLC purification step. This structural information was useful in terms of shedding light on the typical impurity profile of this new chemical entity with the aim to support the early development package for Phase I clinical studies.Journal of pharmaceutical and biomedical analysis 11/2010; 53(3):517-25. · 2.45 Impact Factor -
Article: Exploration of the amine terminus in a novel series of 1,2,4-triazolo-3-yl-azabicyclo[3.1.0]hexanes as selective dopamine D3 receptor antagonists.
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ABSTRACT: A novel series of 1,2,4-triazol-3-yl-azabicyclo[3.1.0]hexanes with high affinity and selectivity for the DA D(3) receptor and excellent pharmacokinetic profiles was recently reported. We also recently discussed the role of the linker associated with the triazole moiety. In this manuscript, we are reporting a detailed exploration of the region of the receptor interacting with the amine terminus of the scaffold wherein SAR and developability data associated with these novel templates was undertaken.Journal of Medicinal Chemistry 10/2010; 53(19):7129-39. · 4.80 Impact Factor -
Article: NMR quantification using an artificial signal.
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ABSTRACT: We have developed QUANTAS (QUANTification by Artificial Signal), which is a software-based protocol for concentration measurement by NMR. QUANTAS is an absolute intensity external standard method for quantification by NMR that compensates for various experimental parameters. It is applicable to all nuclei and modern spectrometers. QUANTAS is demonstrated here for (1)H and (19)F NMR, enabling heteronuclear integrals to be compared. It can be applied using fixed probe tuning, matching and pulse length, for samples with the same effective loading on the probe coil as the appropriate reference spectrum. Otherwise, an optimised tuning and matching approach is adopted for every sample together with explicit PULCON (PUlse Length-based CONcentration measurements) absolute intensity corrections.Magnetic Resonance in Chemistry 10/2010; 48(10):753-62. · 1.44 Impact Factor -
Article: An Efficient Scalable Route for the Synthesis of Enantiomerically Pure tert-Butyl-(1R,4S,6R)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate
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ABSTRACT: An efficient scalable route to synthesize the enantiomerically pure tert-butyl-(1R,4S,6R)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate is described. Compared to the original routes, significant improvements were made by using an innovative approach starting from commercially available chiral lactone. In this approach, one of the key steps described is an elegant epimerization/hydrolysis of the undesired diastereoisomer avoiding tedious purification. The chemistry has been scaled up to produce kilogram amounts of tert-butyl-(1R,4S,6R)-4-(hydroxymethyl)-3-azabicyclo[4.1.0]heptane-3-carboxylate in 43% yield over nine chemical transformations.08/2010; -
Article: Development of a Dynamic Kinetic Resolution for the Isolation of an Intermediate in the Synthesis of Casopitant Mesylate: Application of QbD Principles in the Definition of the Parameter Ranges, Issues in the Scale-Up and Mitigation Strategies
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ABSTRACT: Process development towards the improvement of the manufacturing process of casopitant mesylate (a drug developed by GlaxoSmithKline with activity on the central nervous system) identified a dynamic kinetic resolution opportunity for the improvement of the yield. In this paper, the application of quality by design principles to the DKR is presented together with the issues that were faced during different scale-ups and the at-scale solutions that were implemented.07/2010; -
Article: Application of LC-NMR to the identification of bulk drug impurities in NK1 antagonist GW597599 (vestipitant).
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ABSTRACT: Liquid chromatography-NMR (LC-NMR) spectroscopy was used to obtain detailed information regarding the structure of the major bulk drug impurities present in GW597599 (vestipitant). The one-dimensional (1)H LC-NMR experiments were performed in both continuous and stop-flow modes on a sample of GW597599 (vestipitant) enriched with mother liquor impurities. The information derived from both LC-NMR and LC-MS data provided the structural information of all major impurities. The full characterisation of the impurities by high-resolution NMR spectroscopy was ultimately performed on appropriately synthesised compounds.Magnetic Resonance in Chemistry 07/2010; 48(7):523-30. · 1.44 Impact Factor -
Article: Overall Synthesis of GSK356278: Quick Delivery of a PDE4 Inhibitor Using a Fit-for-Purpose Approach
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ABSTRACT: The family of phosphodiesterase (PDE) enzymes hydrolyse cyclic nucleotides, cAMP and cGMP, leading to their inactivation as intracellular second messengers. Inhibition of these enzymes leads to an elevation of levels of cyclic nucleotides in the cell and prolongs their action on downstream signaling pathways. PDE4, of which there are four subtypes, is widely expressed throughout the brain but is also abundant in the periphery in inflammatory and immune cells, in the gastrointestinal tract, and in cardiac myocytes. GSK356278 1 is a potent, selective, and competitive inhibitor of PDE4 enzymes currently under investigation for the treatment of CNS disorders. The initial synthetic route developed by Medicinal Chemistry Department, used several hazardous and/or expensive reagents and harsh conditions and gave relatively low yields. By targeted process of research and development plus application of analytical techniques to identify byproduct and extensive route scouting, a novel synthetic route for 1 has been developed. This contribution reports the optimisation of the chemical synthesis of 1 to develop a large-scale process suitable for its synthesis.06/2010; -
Article: Identification of a Manufacturing Route of Novel CRF-1 Antagonists Containing a 2,3-Dihydro-1H-pyrrolo[2,3-b]pyridine Moiety
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ABSTRACT: A case study on the synthesis of novel CRF-1 antagonists containing the 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine moiety is presented. The development of ever more efficient synthetic routes allowed the progression of three candidates at the same time. A manufacturing route was identified and successfully demonstrated on a pilot-plant scale to prepare 100 kg of the CRF-1 antagonist GW876008.06/2010; -
Article: Application of the QbD Principles in the Development of the Casopitant Mesylate Manufacturing Process. Process Research Studies for the Definition of the Control Strategy of some Drug Substance-CQAs for Stages 2a, 2b, and 2c
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ABSTRACT: Casopitant was identified as a potent NK1 antagonist by GlaxoSmithKline (GSK). It was selected as part of a wide drug discovery programme within GSK for its potential activities on a number of therapeutic targets such as inflammatory bowel disease, overactive bladder, CNS disorders, and others. The mesylate salt of casopitant was selected for full development. The manufacturing process to casopitant mesylate was developed and optimised by following a Quality by Design approach, whereby a control strategy was developed, underpinned by process understanding and risk analysis, for an enhanced level of quality assurance. Quality process parameters and specifications levels for the Stages 2a, 2b, and 2c are the elements of the control strategy of the manufacturing process discussed in detail in this paper. The Design of Experiment approach has been extensively used to support the definition of the proven acceptable ranges for the process. The aim is to show the process development studies carried out to ensure quality control for the final drug substance.05/2010; -
Article: Synthesis of the NK1 Receptor Antagonist GW597599. Part 3: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine Urea, A Happy End
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ABSTRACT: GW597599 1 is a novel NK-1 antagonist currently under investigation for the treatment of central nervous system disorders and emesis. The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields and produced high levels of waste. Through a targeted process of research and development, application of novel techniques and extensive route scouting, a new synthetic route for GW597599 was developed. This paper reports the optimisation work of the third and last stage in the chemical synthesis of GW597599 and the development of a pilot-plant-suitable process for the manufacturing of optically pure arylpiperazine derivative 1. In particular, the process eliminated the use of triphosgene in the synthesis of an intermediate carbamoyl chloride, substantially enhancing safety, overall yield, and throughput.11/2009; -
Article: Synthesis of the NK1 Receptor Antagonist GW597599. Part 2: Development of a Scalable Route to a Key Chirally Pure Arylpiperazine
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ABSTRACT: GW597599 1 is a novel NK-1 antagonist currently under investigation for the treatment of CNS disorders and emesis. The initial chemical development synthetic route, derived from the one used by medicinal chemistry, involved several hazardous reagents, gave low yields, and produced high levels of wastes. Through a targeted process of research and development, application of novel techniques, and extensive route scouting, a synthetic route for GW597599 has been developed. This paper reports the optimisation work of the second stage in the chemical synthesis of GW597599: the development of a pilot-plant-suitable process for the manufacturing of an optically pure arylpiperazine derivative. In particular, the new process eliminates the need to purchase and store dangerous and expensive borane by generating it in situ and also the need for a chlorinated solvent, thereby improving the safety of the process and substantially reducing the overall waste. The final yield and throughput will be significantly enhanced.05/2009; -
Article: Discovery process and pharmacological characterization of 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) as a potent, selective, and orally active NK1 receptor antagonist.
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ABSTRACT: In an effort to discover novel druglike NK(1) receptor antagonists a new series of suitably substituted C-phenylpiperazine derivatives was identified by an appropriate chemical exploration of related N-phenylpiperazine analogues, with the specific aim to maximize their in vitro affinity and optimize in parallel their pharmacokinetic profile. Among the compounds synthesized, 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) was identified as one of the most in vitro potent and selective NK(1) receptor antagonists ever discovered, showing appropriate pharmacokinetic properties and in vivo activity. On the basis of its preclinical profile, this compound was selected as a drug candidate.Journal of Medicinal Chemistry 05/2009; 52(10):3238-47. · 4.80 Impact Factor -
Article: Synthesis and pharmacological characterization of novel druglike corticotropin-releasing factor 1 antagonists.
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ABSTRACT: To identify new CRF(1) receptor antagonists, an attempt to modify the bis-heterocycle moiety present in the top region of the dihydropyrrole[2,3]pyridine template was made following new pharmacophoric hypothesis on the CRF(1) receptor antagonists binding pocket. In particular, the 2-thiazole ring, present in the previous series of compounds, was replaced by more hydrophilic non aromatic heterocycles able to make appropriate H-bond interactions with amino acid residues Thr192 and Tyr195. This exploration, followed by an accurate analysis of the substitution of the pendant aryl ring, enabled to identify in vitro potent compounds showing excellent pharmacokinetics and outstanding in vivo activity in animal models of anxiety, both in rodents and primates.Journal of Medicinal Chemistry 12/2008; 51(23):7370-9. · 4.80 Impact Factor -
Article: Design, synthesis, and biological evaluation of novel aminobisphosphonates possessing an in vivo antitumor activity through a gammadelta-T lymphocytes-mediated activation mechanism.
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ABSTRACT: A small series of aminobisphosphonates (N-BPs) structurally related to zoledronic acid was synthesized with the aim of improving activity toward activation of human gammadelta T cells and in turn their in vivo antitumor activity. The absence of the 1-OH moiety, together with the position and the different basicity of the nitrogen, appears crucial for antitumor activity. In comparison to zoledronic acid, compound 6a shows a greater ability to activate gammadelta T cells expression (100 times more) and a proapoptotic effect that is better than zoledronic acid. The potent activation of gammadelta T cells, in addition to evidence of the in vivo antitumor activity of 6a, suggests it may be a new potential drug candidate for cancer treatment.Journal of Medicinal Chemistry 11/2008; 51(21):6800-7. · 4.80 Impact Factor -
Article: Design, Synthesis, and Biological Evaluation of Novel Aminobisphosphonates Possessing an in Vivo Antitumor Activity Through a γδ-T Lymphocytes-Mediated Activation Mechanism
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ABSTRACT: A small series of aminobisphosphonates (N-BPs) structurally related to zoledronic acid was synthesized with the aim of improving activity toward activation of human γδ T cells and in turn their in vivo antitumor activity. The absence of the 1-OH moiety, together with the position and the different basicity of the nitrogen, appears crucial for antitumor activity. In comparison to zoledronic acid, compound 6a shows a greater ability to activate γδ T cells expression (100 times more) and a proapoptotic effect that is better than zoledronic acid. The potent activation of γδ T cells, in addition to evidence of the in vivo antitumor activity of 6a, suggests it may be a new potential drug candidate for cancer treatment.Journal of Medicinal Chemistry 10/2008; 51(21):6800. · 4.80 Impact Factor -
Article: 13C bis-labeled pyrroles: a tool for the identification of the rat metabolism of 3-methyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester.
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ABSTRACT: Following the recent disclosure of 3-methyl pyrrole-2,4-dicarboxylic acid 2-propyl ester 4-(1,2,2-trimethyl-propyl) ester as a potent and selective mGluR1 non-competitive antagonist, the use of a doubly (13)C-labeled analogue to identify, and consequently prevent, metabolically labile positions is reported.Bioorganic & Medicinal Chemistry Letters 03/2007; 17(4):969-73. · 2.55 Impact Factor
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2010
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GlaxoSmithKline plc.
London, ENG, United Kingdom
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