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ABSTRACT: A rapid and eco-friendly synthesis of a sulfonamide library under flow conditions is described. The study illustrates an efficient, safe and easily scalable preparation of sulfonamides by use of a mesoreactor apparatus, thus demonstrating the impact of flow technologies within drug discovery. Waste minimization, employment of green media and non toxic reactants are achieved by the optimization of the flow set up and experimental protocol designed to sequentially synthesize primary, secondary and tertiary sulfonamides. Isolation of the products involves only extraction and precipitation affording pure compounds in good to high yields without further purification for biological evaluation.
ACS combinatorial science. 03/2013;
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ABSTRACT: Introduction: The G protein-coupled receptor TGR5 is a key player of the bile acid signaling network, and its activation has been proved to increase the glycemic control, to enhance energy expenditure and to exert anti-inflammatory actions. Accordingly, TGR5 ligands have emerged in drug discovery and preclinical appraisals as promising agents for the treatment of liver diseases, metabolic syndrome and related disorders. Areas covered: Recent advances in the field of TGR5 modulators are reviewed, with a particular attention on patent applications and peer-reviewed publications in the past 6 years. Expert opinion: Activation of TGR5 showed to protect mice from diabesity and insulin resistance, to improve liver functions, as well as to attenuate the development of atherosclerosis. However, although the efficacy of TGR5 agonists in mice is encouraging, further studies are needed to determine their potential in humans and to evaluate carefully the balance between the therapeutic benefits and adverse effects associated with the target. The development of new TGR5 selective ligands to support studies in animal models will surely facilitate the understanding of the complexity of TGR5 signaling network.
Expert Opinion on Therapeutic Patents 10/2012; · 3.57 Impact Factor
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Maura Marinozzi,
Andrea Carotti,
Emanuele Sansone,
Antonio Macchiarulo, Emiliano Rosatelli,
Roccaldo Sardella,
Benedetto Natalini,
Giovanni Rizzo,
Luciano Adorini,
Daniela Passeri,
Francesca De Franco,
Mark Pruzanski,
Roberto Pellicciari
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ABSTRACT: A virtual screening procedure was applied to the discovery of structurally diverse non-steroidal Farnesoid X Receptor (FXR) agonists. From 117 compounds selected by virtual screening, a total of 47 compounds were found to be FXR agonists, with 34 of them showing activity below a concentration of 20 μM. 1H-Pyrazole[3,4-e][1,4]thiazepin-7-one-based hit compound 7 was chosen for hit-to-lead optimization. A large number of 1H-pyrazole[3,4-e][1,4]thiazepin-7-one derivatives was designed, synthesized, and evaluated by a cell-based luciferase transactivation assay for their agonistic activity against FXR. Most of them exhibited low micromolar range of potency and very high efficacy.
Bioorganic & medicinal chemistry 04/2012; 20(11):3429-45. · 2.82 Impact Factor
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ABSTRACT: A new stereoselective synthesis of E-guggulsterone is described starting from androsten-3,17-dione. Protection of the ring A enonic system, followed by regioselective Wittig reaction and C-16 oxidation, affords E-guggulsterone in good yields and high stereoselectivity, making this approach easily accessible and scalable. Moreover, an original normal-phase HPLC method enabling the fast quantitation of the guggulsterone isomeric purity, combined with the suitability for sampling procedures, is detailed. The relying upon the cellulose-based Chiralpak IB column and the chloroform as the "non-standard" component of the eluent mixture, allows to get profitably high chromatographic performances.
Steroids 12/2011; 77(3):250-4. · 2.83 Impact Factor
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ABSTRACT: In a line of research focused on the design, synthesis and development of new bile acid-based compounds, the physico-chemical profile of the molecules must be thoroughly explored and analyzed. In this scenario, a fast and reliable information on the critical micellar concentration (CMC) of specific compounds through a profitable chromatographic parameter can be of aid to rationally direct the synthesis of new molecular entities, mainly during the early stages of the drug-discovery process. The derived 'chromatographic hydrophobicity index' (CHI), usually employed for a fast access to the log P/log D value of physico-chemically diverse compounds and obtained via RP-gradient elution, was for the first time engaged in the bile acid field. Accordingly, 14 unconjugated bile acids harboured with a different number, position and orientation of hydroxy groups, as well as other substituents onto the steroidal backbone and side chain, were selected to build up a calibration curve. Such a collection of compounds was rationally assembled in order to manage an almost continuous range of CMC values (spanning the spectrophotometrically obtained CMCs between 5 and 25 mM). A high degree of correlation between CMC and CHI values was obtained (R(2) and cross-validated R(xv)(2) of the pCMC vs CHI plot equal to 0.975 and 0.966, respectively). A selected new subset of five confidential research bile acids with experimental CMCs in the range 6-19 mM was finally recruited to validate the proposed method. The high statistical quality of the established mathematical model turned out into a very appreciable predictive power.
Analytical and Bioanalytical Chemistry 05/2011; 401(1):267-74. · 3.78 Impact Factor
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Roberto Pellicciari,
Antimo Gioiello,
Antonio Macchiarulo,
Charles Thomas, Emiliano Rosatelli,
Benedetto Natalini,
Roccaldo Sardella,
Mark Pruzanski,
Aldo Roda,
Elisabetta Pastorini,
Kristina Schoonjans,
Johan Auwerx
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ABSTRACT: In the framework of the design and development of TGR5 agonists, we reported that the introduction of a C(23)(S)-methyl group in the side chain of bile acids such as chenodeoxycholic acid (CDCA) and 6-ethylchenodeoxycholic acid (6-ECDCA, INT-747) affords selectivity for TGR5. Herein we report further lead optimization efforts that have led to the discovery of 6alpha-ethyl-23(S)-methylcholic acid (S-EMCA, INT-777) as a novel potent and selective TGR5 agonist with remarkable in vivo activity.
Journal of Medicinal Chemistry 12/2009; 52(24):7958-61. · 4.80 Impact Factor
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ABSTRACT: Bile acids regulate nongenomic actions through the activation of TGR5, a membrane receptor that is G protein-coupled to the induction of adenylate cyclase. In this work, a training set of 43 bile acid derivatives is used to develop a molecular interaction field analysis (MFA) and a 3D-quantitative structure-activity relationship study (3D-QSAR) of TGR5 agonists. The predictive ability of the resulting model is evaluated using an external set of compounds with known TGR5 activity, and six bile acid derivatives whose unknown TGR5 activity is herein assessed with in vitro luciferase assay of cAMP formation. The results show a good predictive model and indicate a statistically relevant degree of correlation between the TGR5 activity and the molecular interaction fields produced by discrete positions of the bile acid scaffold. This information is instrumental to extend on a quantitative basis the current structure-activity relationships of bile acids as TGR5 modulators and will be fruitful to design new potent and selective agonists of the receptor.
Journal of Chemical Information and Modeling 09/2008; 48(9):1792-801. · 4.68 Impact Factor
