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Publications 2010

The metabolism and disposition of a potent inhibitor of hepatitis C virus NS3/4A protease.

By Monteagudo E; Fonsi M; Chu X; Bleasby K; Evers R; Pucci V; Orsale M V; Cianetti S; Ferrara M; Harper S; et al
From Xenobiotica; the fate of foreign compounds in biological systems (2010), 40(12), 826-39, Language: English, Database: MEDLINE

Compound A
((1aR,5S,8S,10R,22aR)-5-tert-butyl-N-{(1R,2S)-1-[(cyclopropylsulfonyl)carbamoyl]-2-ethenylcyclopropyl}-14-methoxy-3,6-dioxo-1,1a,3,4,5,6,9,10,18,19,20,21,22,22a-tetradecahydro-8H-7,10-methanocyclopropa[18,19][1,10,3,6]dioxadiazacyclononadecino[12,11-b]quinoline-8-carboxamide) is a prototype of a series of subnanomolar inhibitors of genotypes 1, 2, and 3 hepatitis C virus (HCV) NS3/4A proteases. HCV NS3/4A protease inhibitors have demonstrated high antiviral effects in patients with chronic HCV infection and are likely to form a key component of future HCV therapy. Compound A showed excellent liver exposure in rats, which is essential for compounds intended to treat HCV. The compound was mainly eliminated intact in bile and showed greater than dose proportional systemic exposure in rats. Compound A demonstrated time- and temperature-dependent uptake into rat and human hepatocytes and proved to be a substrate for rat hepatic uptake transporter Oatp1b2 and for human hepatic uptake transporters OATP1B1 and OATP1B3. The liver selectivity observed for this compound is likely to be due to transporter-mediated hepatic uptake together with moderate passive permeability. Metabolism was mainly CYP3A-mediated and generated a reactive epoxide on the vinylcyclopropyl sulfonamide moiety that could be quenched by glutathione. Similar metabolic profiles of Compound A were obtained in liver microsomes of rats and humans. The oral bioavailability at 5 mg/kg was low due to extensive hepatic first-pass effect but clearly the intestinal absorption was enough to deliver a high amount of the compound to the liver. The metabolism and disposition properties of Compound A are particularly attractive to support its evaluation as a drug candidate for the treatment of hepatitis C.

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Development of 2-pyrrolidinyl-N-methyl pyrimidones as potent and orally bioavailable HIV integrase inhibitors.

By Ferrara, Marco; Fiore, Fabrizio; Summa, Vincenzo; Gardelli, Cristina
From Bioorganic & Medicinal Chemistry Letters (2010), 20(17), 5031-5034. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2010.07.042

A series of 2-pyrrolidinyl-N-Me pyrimidones HIV integrase inhibitors has been explored leading to the identification of deriv. 13, which showed high activity at inhibiting viral replication in cell culture, favorable pharmacokinetic profile in two preclin. species, and an attractive profile against a panel of HIV-integrase mutants.

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A vaccine targeting telomerase enhances survival of dogs affected by B-cell lymphoma.

By Peruzzi, Daniela; Gavazza, Alessandra; Mesiti, Giuseppe; Lubas, George; Scarselli, Elisa; Conforti, Antonella; Bendtsen, Claus; Ciliberto, Gennaro; La Monica, Nicola; Aurisicchio, Luigi
From Molecular Therapy (2010), 18(8), 1559-1567. Language: English, Database: CAPLUS, DOI:10.1038/mt.2010.104

Canine cancers occur with an incidence similar to that of humans and share many features with human malignancies including histol. appearance, tumor genetics, biol. behavior, and response to conventional therapies. As obsd. in humans, the telomerase reverse transcriptase (TERT) activity is largely confined to tumor tissues and absent in the majority of normal dog tissues. Therefore, dog TERT (dTERT) can constitute a valid target for translational cancer immunotherapy. We have evaluated the ability of adenovirus serotype 6 (Ad6) and DNA electroporation (DNA-EP) to induce immune responses against dTERT in dogs affected by malignant lymphoma (ML). The vaccine was combined with std. chemotherapy regimen [cyclophosphamide, vincristine, prednisone (COP)]. dTERT-specific immune response was induced in 13 out of 14 treated animals (93%) and remained detectable and long-lasting with the absence of autoimmunity or other side effects. Most interestingly, the survival time of vaccine/Chemo-treated dogs was significantly increased over historic controls of Chemo-treated animals (> 97.8 vs. 37 wk, resp., P = 0.001). Our results show that Ad6/DNA-EP-based cancer vaccine against dTERT overcomes host immune tolerance, should be combined with chemotherapy, induces long-lasting immune responses, and significantly prolongs the survival of ML canine patients. These data support further evaluation of this approach in human clin. trials.

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Immunological markers of cancer vaccine efficacy and their clinical relevance.

Cipriani B. (2009)
Biomark Med. 2009 Jun;3(3):253-64.

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Allosteric inhibitors of hepatitis C virus NS5B polymerase thumb domain site II: structure-based design and synthesis of new templates.

By Malancona, Savina; Donghi, Monica; Ferrara, Marco; Martin Hernando, Jose I.; Pompei, Marco; Pesci, Silvia; Ontoria, Jesus M.; Koch, Uwe; Rowley, Michael; Summa, Vincenzo
From Bioorganic & Medicinal Chemistry (2010), 18(8), 2836-2848. Language: English, Database: CAPLUS, DOI:10.1016/j.bmc.2010.03.024

Chronic hepatitis C virus (HCV) infections are a significant medical problem worldwide. The NS5B Polymerase of HCV plays a central role in virus replication and is a prime target for the discovery of new treatment options. We recently disclosed 1H-benzo[de]isoquinoline-1,3(2H)-diones as allosteric inhibitors of NS5B Polymerase. Structural and SAR information guided us in the modification of the core structure leading to new templates with improved activity and toxicity/activity window.

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Enhancement of intestinal absorption of 2-methyl cytidine prodrugs.

By Cianetti, Simona; Cooper, Vincent Brett; Attenni, Barbara; Pucci, Vincenzo; Fiore, Fabrizio; Giuliano, Claudio; Laufer, Ralph; Gardelli, Cristina; Monteagudo, Edith; Narjes, Frank; et al
From Drug Delivery (2010), 17(4), 214-222. Language: English, Database: CAPLUS, DOI:10.3109/10717541003667814

The purpose of this study was to investigate the in vivo absorption enhancement of a nucleoside (phosphoramidate prodrug of 2′-methyl-cytidine) anti-viral agent of proven efficacy by means of intestinal permeation enhancers. Natural nucleosides are hydrophilic mols. that do not rapidly penetrate cell membranes by diffusion and their absorption relies on specialized transporters. Therefore, the oral absorption of nucleoside prodrugs and the target organ concn. of the biol. active nucleotide can be limited due to poor permeation across the intestinal epithelium. In the present study, the specificity, concn. dependence, and effect of four classes of absorption promoters, i.e. fatty acids, steroidal detergents, mucoadhesive polymers, and secretory transport inhibitors, were evaluated in a rat in vivo model. Sodium caprate and α-tocopheryl-polyethyleneglycol-1000-succinate (TPGS) showed a significant effect in increasing liver concn. of nucleotide (5-fold). These results suggested that both excipients might be suited in a controlled release matrix for the synchronous release of the drug and absorption promoter directly to the site of absorption and highlights that the effect is strictly dependent on the absorption promoter dose. The feasibility of such a formulation approach in humans was evaluated with the aim of developing a solid dosage form for the peroral delivery of nucleosides and showed that these excipients do provide a potential valuable tool in pre-clin. efficacy studies to drive discovery programs forward.

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Identification and SAR of novel pyrrolo[1,2-a]pyrazin-1(2H)-one derivatives as inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1).

By Pescatore, Giovanna; Branca, Danila; Fiore, Fabrizio; Kinzel, Olaf; Bufi, Laura Llauger; Muraglia, Ester; Orvieto, Federica; Rowley, Michael; Toniatti, Carlo; Torrisi, Caterina; et al
From Bioorganic & Medicinal Chemistry Letters (2010), 20(3), 1094-1099. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2009.12.026

The discovery of a novel series of pyrrolo[1,2-a]pyrazin-1(2H)-one PARP inhibitors is described. Optimization led to compds. that display excellent PARP-1 enzyme potency and inhibit the proliferation of BRCA deficient cells in the low double-digit nanomolar range showing excellent selectivity over BRCA proficient cancer cells.

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Development of substituted 6-[4-fluoro-3-(piperazin-1-ylcarbonyl)benzyl]-4,5-dimethylpyridazin-3(2H)-ones as potent poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors active in BRCA deficient cells.

By Ferrigno, Federica; Branca, Danila; Kinzel, Olaf; Lillini, Samuele; Llauger Bufi, Laura; Monteagudo, Edith; Muraglia, Ester; Rowley, Michael; Schultz-Fademrecht, Carsten; Toniatti, Carlo; et al
From Bioorganic & Medicinal Chemistry Letters (2010), 20(3), 1100-1105. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2009.11.087

We describe an extensive SAR study in the 6-[4-fluoro-3-(substituted)benzyl]-4,5-dimethylpyridazin-3(2H)-one series which led to the identification of potent PARP-1 inhibitors, capable of inhibiting the proliferation of BRCA-1 deficient cancer cells in the low nanomolar range, and displaying >100-fold selectivity over the BRCA wild type counterparts. The series of compds. was devoid of hERG channel activity, and CYP inhibition and induction liabilities. Several analogs were stable in rat and human liver microsomes and displayed moderate rat clearance, with urinary excretion of parent as the major route of elimination.

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Discovery and SAR of novel, potent and selective hexahydrobenzonaphthyridinone inhibitors of poly(ADP-ribose)polymerase-1 (PARP-1).

By Torrisi, Caterina; Bisbocci, Monica; Ingenito, Raffaele; Ontoria, Jesus M.; Rowley, Michael; Schultz-Fademrecht, Carsten; Toniatti, Carlo; Jones, Philip
From Bioorganic & Medicinal Chemistry Letters (2010), 20(2), 448-452. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2009.12.002

A novel hexahydrobenzonaphthyridinone PARP-1 pharmacophore is reported. Subsequent SAR exploration around this scaffold led to selective PARP-1 inhibitors with low nanomolar enzyme potency, displaying good cellular activity and promising rat PK properties.

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Synthesis and biological evaluation of substituted 2-phenyl-2H-indazole-7-carboxamides as potent poly(ADP-ribose) polymerase (PARP) inhibitors.

By Scarpelli, Rita; Boueres, Julia K.; Cerretani, Mauro; Ferrigno, Federica; Ontoria, Jesus M.; Rowley, Michael; Schultz-Fademrecht, Carsten; Toniatti, Carlo; Jones, Philip
From Bioorganic & Medicinal Chemistry Letters (2010), 20(2), 488-492. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2009.11.127

Synthesis and biological evaluation of substituted 2-phenyl-2H-indazole-7-carboxamides as potent poly(ADP-ribose) polymerase (PARP) inhibitorsA potent series of substituted 2-phenyl-2H-indazole-7-carboxamides were synthesized and evaluated as inhibitors of poly (ADP-ribose) polymerase (PARP). This extensive SAR exploration culminated with the identification of substituted 5-fluoro-2-phenyl-2H-indazole-7-carboxamide analog I which displayed excellent PARP enzyme inhibition with IC50 = 4 nM, inhibited proliferation of cancer cell lines deficient in BRCA-1 with CC50 = 42 nM and showed encouraging pharmacokinetic properties in rats compared to the lead 6.

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Telomerase and HER-2/neu as targets of genetic cancer vaccines in dogs.

By Peruzzi, Daniela; Mesiti, Giuseppe; Ciliberto, Gennaro; La Monica, Nicola; Aurisicchio, Luigi
From Vaccine (2010), 28(5), 1201-1208. Language: English, Database: CAPLUS, DOI:10.1016/j.vaccine.2009.11.031

Pet dogs represent a valuable pre-clin. model to assess the efficacy of oncol. drugs. Addnl., canine cancers occur with an incidence similar to that of humans and share many features with human malignancies including histol. appearance, tumor genetics, biol. behavior and response to conventional therapies. The telomerase reverse transcriptase (TERT) is reactivated in most of human and dog tumors. Similarly, HER-2/neu oncoprotein is overexpressed in a proportion of canine breast cancers. Therefore, TERT and HER-2/neu can constitute valid tumor assocd. antigens (TAA), suitable targets for translational cancer immunotherapy in dogs. In this study, we have evaluated the ability of DNA electroporation (DNA-EP) and Adenovirus serotype 6 (Ad6) to induce immune responses against dog TERT (dTERT) and HER-2/neu in healthy dogs. Vaccination was effective in all treated animals and the adaptive immune response remained detectable and long-lasting in the absence of autoimmunity or other side-effects. Our results show that DNA-EP/Ad6-based cancer vaccine induces adaptive immune responses against TAA in canine subjects and support further evaluation of this approach in cancer dog patients.

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Novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease by P3 succinamide fragment depeptidization strategy.

By Pompei, Marco; Di Francesco, Maria Emilia; Pesci, Silvia; Koch, Uwe; Vignetti, Sue Ellen; Veneziano, Maria; Pace, Paola; Summa, Vincenzo
From Bioorganic & Medicinal Chemistry Letters (2010), 20(1), 168-174. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2009.11.005

Hepatitis C represents a serious worldwide health-care problem. Recently, we have disclosed a novel class of P2-P4 macrocyclic inhibitors of NS3/4A protease contg. a carbamate functionality as capping group at the P3 N-terminus. Herein we report our work aimed at further depeptidizing the P3 region by replacement of the urethane function with a succinamide motif. This peptidomimetic approach has led to the discovery of novel P2-P4 macrocyclic inhibitors of HCV NS3/4A protease with sub-nanomolar enzyme affinities. In addn. to being potent inhibitors of HCV subgenomic replication, optimized analogs within this series have also presented attractive PK properties and showed promising liver levels in rat following oral administration.

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Novel potent apoA-I peptide mimetics that stimulate cholesterol efflux and pre-β particle formation in vitro

By Ingenito, Raffaele; Burton, Charlotte; Langella, Annunziata; Chen, Xun; Zytko, Karolina; Pessi, Antonello; Wang, Jun; Bianchi, Elisabetta
From Bioorganic & Medicinal Chemistry Letters (2010), 20(1), 236-239. Language: English, Database: CAPLUS, DOI:10.1016/j.bmcl.2009.10.128

Reverse cholesterol transport (RCT) is believed to be the primary mechanism by which HDL and its major protein apoA-I protect against atherosclerosis. Starting from the inactive 22-amino acid peptide representing the consensus sequence of the class A amphipathic helical repeats of apoA-I, we designed novel peptides able to mobilize cholesterol from macrophages in vitro, and to stimulate the formation of nascent HDL’ particles, with potency comparable to the entire apoA-I protein.

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Turbulent flow chromatography TFC-tandem mass spectrometry supporting in vitro/vivo studies of NCEs in high throughput fashion.

By Verdirame, Maria; Veneziano, Maria; Alfieri, Anna; Di Marco, Annalise; Monteagudo, Edith; Bonelli, Fabio
From Journal of Pharmaceutical and Biomedical Analysis (2010), 51(4), 834-841. Language: English, Database: CAPLUS, DOI:10.1016/j.jpba.2009.10.005

Turbulent Flow Chromatog. (TFC) is a powerful approach for online extn. in bioanal. studies. It improves sensitivity and reduces sample prepn. time, two factors that are of primary importance in drug discovery. In this paper the application of the ARIA system to the anal. support of in vivo pharmacokinetics (PK) and in vitro drug metab. studies is described, with an emphasis in high throughput optimization. For PK studies, a comparison between acetonitrile plasma protein pptn. (APPP) and TFC was carried out. The authors’ optimized TFC methodol. gave better S/N ratios and lower limit of quantification (LOQ) than conventional procedures. A robust and high throughput anal. method to support hepatocyte metabolic stability screening of new chem. entities was developed by hyphenation of TFC with mass spectrometry. An in-loop diln. injection procedure was implemented to overcome one of the main issues when using TFC, that is the early elution of hydrophilic compds. that renders low recoveries. A comparison between off-line solid phase extn. (SPE) and TFC was also carried out, and recovery, sensitivity (LOQ), matrix effect and robustness were evaluated. The use of two parallel columns in the configuration of the system provided a further increase of the throughput.

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