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1. Good Laboratory Practice Preclinical Safety Studies for GSK2696273 (MLV Vector-Based Ex Vivo Gene Therapy for Adenosine Deaminase Deficiency Severe Combined Immunodeficiency) in NSG Mice

Author

Michela Vezzoli, Franck Chanut, Paola Albertini, Elena Draghici, Raisa Jofra Hernandez, Aisha V. Sauer, Jonathan Appleby, Melanie Nord, Alessandro Aiuti, Patrizia Cristofori, Jan Klapwijk, Jane Richards, Nicola Carriglio, Hazel Staton, Rhiannon Lowe, Carriglio, N., Klapwijk, J., Hernandez, R. J., Vezzoli, M., Chanut, F., Lowe, R., Elena, D., Nord, M., Albertini, P., Cristofori, P., Richards, J., Staton, H., Appleby, J., Aiuti, A., and Sauer, A. V.

Subjects
Male, 0301 basic medicine, Adenosine Deaminase, Genetic enhancement, GLP, Genetic Vectors, Drug Evaluation, Preclinical, CD34, Mice, SCID, Viral vector, Mice, 03 medical and health sciences, Adenosine deaminase, Agammaglobulinemia, Mice, Inbred NOD, Animals, Humans, media_common.cataloged_instance, Medicine, Tissue Distribution, European union, retroviral vector, biodistribution, Genetics (clinical), media_common, Severe combined immunodeficiency, biology, business.industry, Gene Transfer Techniques, Correction, Genetic Therapy, medicine.disease, gene therapy, Adenosine deaminase deficiency, Haematopoiesis, ADA-SCID, 030104 developmental biology, Immunology, biology.protein, Female, Severe Combined Immunodeficiency, Laboratories, business
Abstract

GSK2696273 (autologous CD34+ cells transduced with retroviral vector that encodes for the human adenosine deaminase [ADA] enzyme) is a gamma-retroviral ex vivo gene therapy of bone marrow-derived CD34+ cells for the treatment of adenosine deaminase deficiency severe combined immunodeficiency (ADA-SCID). ADA-SCID is a severe monogenic disease characterized by immunologic and nonimmunologic symptoms. Bone-marrow transplant from a matched related donor is the treatment of choice, but it is available for only a small proportion of patients. Ex vivo gene therapy of patient bone-marrow CD34+ cells is an alternative treatment. In order to prepare for a marketing authorization application in the European Union, preclinical safety studies in mice were requested by the European Medicines Agency (EMA). A pilot study and a main biodistribution study were performed according to Good Laboratory Practice (GLP) at the San Raffaele Telethon Institute for Gene Therapy test facility. In the main study, human umbilical cord blood (UCB)-derived CD34+ cells were transduced with gamma-retroviral vector used in the production of GSK2696273. Groups of 10 male and 10 female NOD-SCID gamma (NSG) mice were injected intravenously with a single dose of transduced- or mock-transduced UCB CD34+ cells, and they were observed for 4 months. Engraftment and multilineage differentiation of blood cells was observed in the majority of animals in both groups. There was no significant difference in the level of chimerism between the two groups. In the gene therapy group, vector was detectable in lymphohemopoietic and nonlymphohemopoietic tissues, consistent with the presence of gene-modified human hematopoietic donor cells. Given the absence of relevant safety concerns in the data, the nonclinical studies and the clinical experience with GSK2696273 supported a successful application for market authorization in the European Union for the treatment of ADA-SCID patients, for whom no suitable human leukocyte antigen-matched related donor is available.

Published
2017
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2. Cassette Dosing for Pharmacokinetic Screening in Drug Discovery: Comparison of Clearance, Volume of Distribution, Half-Life, Mean Residence Time, and Oral Bioavailability Obtained by Cassette and Discrete Dosing in Rats

Author

Rakesh Nagilla, Jeff J. McAtee, Melanie Nord, and Larry J. Jolivette

Subjects
Male, Volume of distribution, Chromatography, Chemistry, Administration, Oral, Biological Availability, Pharmaceutical Science, Half-life, PK Parameters, Pharmacology, Rats, Bioavailability, Rats, Sprague-Dawley, Sprague dawley, Pharmacokinetics, Tandem Mass Spectrometry, Oral administration, Animals, Female, Dosing, Chromatography, Liquid, Half-Life
Abstract

The purpose of this investigation was to compare selected pharmacokinetic (PK) parameters obtained by cassette and discrete dosing of compounds in rats. The concordance of PK properties obtained by the two dosing strategies was evaluated for 116 compounds representing various therapeutic programs and diverse chemical structures. The correspondence between cassette- and discrete-dosing-derived PK properties was examined semiquantitatively and qualitatively. For semiquantitative comparison, compounds with cassette-to-discrete PK parameter ratios between 0.5 and 2 (inclusive) were considered to be in agreement. For qualitative comparison, compounds were divided into three categories (low, moderate, and high) based on the value of the PK parameter; compounds that fell into the same category following cassette and discrete dosing were considered to be in agreement. Of the 116 compounds evaluated, 89%, 91%, 80%, and 91% of the compounds were semiquantitatively equivalent for the intravenous PK parameters of clearance (CL), volume of distribution (Vdss), terminal elimination plasma half-life (HL), and mean residence time (MRT), respectively, whereas 79%, 80%, 79%, and 72% were qualitatively similar for CL, Vdss, MRT, and terminal elimination plasma HL, respectively. Following oral administration, bioavailability concordance was 72% when assessed qualitatively and 78% when determined semiquantitatively. Results from these analyses indicate that a cassette dosing strategy is a viable approach to screen compounds for PK properties within a drug discovery setting. © 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3862–3874, 2011

Published
2011
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3. Discovery of novel aminothiadiazole amides as selective EP(3) receptor antagonists

Author

Jian Jin, Xiaoping Hou, Charlene W. Wu, Dwight M. Morrow, Richard M. Edwards, Zhimin Du, Ning Wang, Rakesh Nagilla, Mark Pullen, Mark A. Hilfiker, Melanie Nord, A C Sulpizio, Jon-Paul Jaworski, and Harvey E. Fries

Subjects
Chemistry, Pharmaceutical, education, Clinical Biochemistry, Pharmaceutical Science, Administration, Oral, Pharmacology, Biochemistry, Rats, Sprague-Dawley, Structure-Activity Relationship, Dogs, In vivo, Drug Discovery, Thiadiazoles, Animals, Humans, Receptors, Prostaglandin E, Receptor, Molecular Biology, Aminothiadiazole, Molecular Structure, Chemistry, Organic Chemistry, Antagonist, Amides, humanities, In vitro, Rats, Models, Chemical, Drug Design, Benzene derivatives, Receptors, Prostaglandin E, EP3 Subtype, Molecular Medicine, Functional activity, Ep receptor, Protein Binding
Abstract

This Letter discloses a series of 2-aminothiadiazole amides as selective EP 3 receptor antagonists. SAR optimization resulted in compounds with excellent functional activity in vitro. In addition, efforts to optimize DMPK properties in the rat are discussed. These efforts have resulted in the identification of potent, selective EP 3 receptor antagonists with excellent DMPK properties suitable for in vivo studies.

Published
2009

4. Design and synthesis of orally bioavailable serum and glucocorticoid-regulated kinase 1 (SGK1) inhibitors

Author

Marlys Hammond, David G. Washburn, Angela Smallwood, Tram H. Hoang, Nicholas J. Laping, Rebecca Trejo, Hiroko Nakamura, James S. Frazee, Martha S. Head, Scott K. Thompson, Kendra E. Hightower, Charlene Wu, Rakesh Nagilla, Jaclyn R. Patterson, Melanie Nord, Walter Trizna, Baoguang Zhao, Sharada Manns, Leonard M. Azzarano, and Christine G. Schnackenberg

Subjects
Stereochemistry, Carboxylic acid, Chemistry, Pharmaceutical, Clinical Biochemistry, Glucuronidation, Molecular Conformation, Pharmaceutical Science, Administration, Oral, Biological Availability, Protein Serine-Threonine Kinases, Biochemistry, Immediate-Early Proteins, chemistry.chemical_compound, Acetic acid, Inhibitory Concentration 50, Structure-Activity Relationship, Glucuronic Acid, Drug Discovery, Animals, Carboxylate, Enzyme Inhibitors, Molecular Biology, Glucocorticoids, Protein Kinase Inhibitors, Benzoic acid, chemistry.chemical_classification, biology, Bicyclic molecule, Organic Chemistry, Glucuronic acid, Rats, chemistry, Models, Chemical, Enzyme inhibitor, Drug Design, biology.protein, Molecular Medicine
Abstract

The lead serum and glucocorticoid-related kinase 1 (SGK1) inhibitors 4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-3-yl)benzoic acid (1) and {4-[5-(2-naphthalenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl]phenyl}acetic acid (2) suffer from low DNAUC values in rat, due in part to formation and excretion of glucuronic acid conjugates. These PK/glucuronidation issues were addressed either by incorporating a substituent on the 3-phenyl ring ortho to the key carboxylate functionality of 1 or by substituting on the group in between the carboxylate and phenyl ring of 2. Three of these analogs have been identified as having good SGK1 inhibition potency and have DNAUC values suitable for in vivo testing.

Published
2009

5. Synthesis and SAR of amino acid-derived heterocyclic progesterone receptor full and partial agonists

Author

Jaclyn R. Patterson, Scott K. Thompson, Harvey E. Fries, Eugene T. Grygielko, Walter Trizna, Tram H. Hoang, Jeffrey D. Bray, Nicholas J. Laping, Douglas J. Minick, Melanie Nord, Lindsay E. Glace, Rakesh Nagilla, Marlys Hammond, Sharada Manns, and David G. Washburn

Subjects
Agonist, medicine.drug_class, Stereochemistry, Clinical Biochemistry, Triazole, Pharmaceutical Science, Tetrazoles, Biochemistry, Chemical synthesis, Partial agonist, chemistry.chemical_compound, Structure-Activity Relationship, Drug Discovery, Progesterone receptor, medicine, Structure–activity relationship, Animals, Tetrazole, Amino Acids, Molecular Biology, chemistry.chemical_classification, Organic Chemistry, Amino acid, Rats, chemistry, Molecular Medicine, Receptors, Progesterone
Abstract

Two classes of amino acid-derived heterocyclic progesterone receptor ligands were developed to address the metabolic issues posed by the dimethyl amide functionality of the lead compound (1). The tetrazole-derived ligands behaved as potent partial agonists, while the 1,2,4-triazole ligands behaved as potent full agonists.

Published
2009

6. Synthesis and SAR of potent LXR agonists containing an indole pharmacophore

Author

Derek J. Parks, Angela Smallwood, Nino Campobasso, David G. Washburn, Melanie Nord, Tram H. Hoang, Michael Jaye, Scott K. Thompson, Christopher P. Evans, Christine L. Webb, Chaya Duraiswami, and Kelly A. Frank

Subjects
Agonist, Indoles, Tertiary amine, Stereochemistry, medicine.drug_class, Clinical Biochemistry, Molecular Conformation, Pharmaceutical Science, Administration, Oral, Receptors, Cytoplasmic and Nuclear, Crystallography, X-Ray, digestive system, Biochemistry, Mice, Structure-Activity Relationship, Drug Discovery, polycyclic compounds, medicine, Animals, Combinatorial Chemistry Techniques, Liver X receptor, Molecular Biology, Liver X Receptors, Indole test, Molecular Structure, Chemistry, Pulmonary inflammation, Macrophages, Organic Chemistry, food and beverages, Orphan Nuclear Receptors, Rats, DNA-Binding Proteins, Cholesterol, Nuclear receptor, Molecular Medicine, lipids (amino acids, peptides, and proteins), Pharmacophore
Abstract

A novel series of 1H-indol-1-yl tertiary amine LXR agonists has been designed. Compounds from this series were potent agonists with good rat pharmacokinetic parameters. In addition, the crystal structure of an LXR agonist bound to LXRα will be disclosed.

Published
2008

7. Abstracts from the 10th C1-inhibitor deficiency workshop

Author

Alvin H. Schmaier, Marco Cicardi, Avner Reshef, Dumitru Moldovan, Attila Mócsai, Margarita López-Trascasa, Alberto López Lera, Nancy J. Brown, Anastasios E. Germenis, Rafael Filippelli-Silva, Diego A. Duarte, Renan P. Martin, Camila L. Veronez, Michel Bouvier, Michael Bader, Claudio M. Costa-Neto, João Bosco Pesquero, Xavier Charest-Morin, François Marceau, Georges-É. Rivard, Arnaud Bonnefoy, Éric Wagner, Márta L. Debreczeni, Zsuzsanna Németh, Erika Kajdácsi, Endre Schwaner, László Cervenak, Gábor Oroszlán, András Szilágyi, Ráhel Dani, Péter Závodszky, Péter Gál, József Dobó, Jacques Hébert, Matthieu Vincent, Jean-Nicolas Boursiquot, Hugo Chapdeleine, Marylin Desjardins, Benoit Laramée, Rémi Gagnon, Nancy Payette, Oleksandra Lepeshkina, Delphine Charignon, Arije Ghannam, Denise Ponard, Christian Drouet, Kusumam Joseph, Baby G. Tholanikunnel, Daniel J. Sexton, Allen P. Kaplan, Stefania Loffredo, Maria Bova, Anne Lise Ferrara, Angelica Petraroli, Chiara Suffritti, Nóra Veszeli, Andrea Zanichelli, Henriette Farkas, Gianni Marone, Samuel Luyasu, Bertrand Favier, Ludovic Martin, Kinga Viktória Kőhalmi, György Temesszentandrási, Katalin Várnai, Lilian Varga, Bruce L. Zuraw, Annette Feussner, Michael A. Tortorici, Dipti Pawaskar, Huamin Henry Li, John Anderson, Jonathan A. Bernstein, Ying Zhang, Ingo Pragst, on behalf of COMPACT investigators, Emel Aygören-Pürsün, Kraig Jacobson, Jim Christensen, Arthur Van Leerberghe, Yi Wang, Jennifer Schranz, Inmaculada Martinez-Saguer, Daniel Soteres, Urs Steiner, Vesna Grivcheva Panovska, William Rae, Werner Aberer, Aarnoud Huissoon, Anette Bygum, Markus Magerl, Jochen Graff, Hilary Longhurst, Ramón Lleonart, Lei Fang, Melanie Cornpropst, Desiree Clemons, Amanda Mathis, Phil Collis, Sylvia Dobo, William P. Sheridan, Marcus Maurer, Marc A. Riedl, Timothy Craig, Aleena Banerji, Mustafa Shennak, William Yang, Jovanna Baptista, Paula Busse, Ira Kalfus, Andrew McDonald, Shawn Qian, Anthony Roberts, Con Panousis, Tim Green, Andreas Gille, Maria Zamanakou, Gedeon Loules, Dorottya Csuka, Fotis Psarros, Faidra Parsopoulou, Matthaios Speletas, Davide Firinu, Tiziana Maria Angela De Pasquale, Alessandra Zoli, Anna Radice, Stefano Pizzimenti, Emmanouil Manoussakis, George N. Konstantinou, Valeria Bafunno, Vincenzo Montinaro, Mauro Cancian, Maurizio Margaglione, Konrad Bork, Karin Wulff, Guenther Witzke, Jochen Hardt, Laurence Bouillet, Teresa Caballero, Anete S. Grumach, Christelle Pommie, Irmgard Andresen, Carmen Escuriola Ettingshausen, Zeynep Gutowski, Karin Andritschke, Richard Linde, Noémi Andrási, Tamás Szilágyi, Iris Leibovich-Nassi, Christine Symons, John Dempster, Isabelle Boccon-Gibod, Anne Pagnier, Audrey Lehmann, Kristian B. Kreiberg, Sandra A. Nieto, Raquel Martins, Renata Martins, Alejandra Menendez, Solange O. R. Valle, Margarita Olivares, Maria E. Hernandez-Landeros, Elma Nievas, Natalia Fili, Olga M. Barrera, René Bailleau, Ana Maria Gallardo-Olivos, Masumi Grau, Julian Rodriguez-Galindo, Marlon J. O. Carabantes, Edison Zapata-Venegas, Mario Martinez Alfonso, Maria Rosario-Grauert, Manuel Ratti, Daniel Vaszquez, Dario Josviack, Luis Fernando Landivar-Salinas, Oscar M. E. Calderón-Llosa, Rolando Campilay-Sarmiento, Pablo Raby, Jose Fabiani, William R. Lumry, Henrike Feuersenger, Douglas J. Watson, Thomas Machnig, on behalf of the Investigators of the COMPACT study, Donatella Lamacchia, Adriana Hernanz, Ana Alvez, Mariana Lluncor, Maria Pedrosa, Rosario Cabañas, Nieves Prior, Patrik Nordenfelt, Mats Nilsson, Anders Lindfors, Carl-Fredrik Wahlgren, Janne Björkander, Roman Hakl, Pavel Kuklínek, Irena Krčmová, Jana Hanzlíková, Martina Vachová, Radana Zachová, Marta Sobotková, Jana Strenková, Jiří Litzman, Maria Palasopoulou, Gerasimina Tsinti, Panagiota Gianni, Maria Kompoti, Sofia Garrido, Wojciech Dyga, Anna Bogdali, Aleksander Obtułowicz, Mikolajczyk Tomasz, Ewa Czarnobilska, Krystyna Obtulowicz, Teofila Książek, Anna Koncz, Dominik Gulyás, Maria Staevska, Milos Jesenak, Katarina Hrubiskova, L. Bellizzi, A. Relan, Maddalena A. Wu, Antonio Castelli, Riccardo Colombo, Gianmarco Podda, Marta Del Medico, Emanuele Catena, Francesco Casella, Francesca Perego, Nada Afifi Afifi, Eleonora Tobaldini, Nicola Montano, for the IOS Study Group, Marta Sánchez-Jareño, Marcin Stobiecki, Krystyna Obtułowicz, Irina Guryanova, Ekaterina Polyakova, Viktar Lebedz, Andrej Salivonchik, Svetlana Aleshkevich, Mikhail Belevtsev, Melanie Nordmann-Kleiner, Susanne Trainotti, Janina Hahn, Jens Greve, Liudmyla Zabrodska, Maria L. Oliva Alonso, Rosangela P. Tórtora, Alfeu T. França, Marcia G. Ribeiro, Lisa Fu, Amin Kanani, Gina Lacuesta, Susan Waserman, Stephen Betschel, Melissa I. Espinosa, Francisco A. Contreras, Martin Hrubisko, Ludmila Vavrova, Peter Banovcin, Maryam Ayazi, Mohammad Reza Fazlollahi, Shiva Saghafi, Sajedeh Mohammadian, Susan Nabilou Deshiry, Kiana Bidad, Raheleh Shokouhi Shoormasti, Iraj Mohammadzadeh, Mohammad Hassan Bemanian, Seyed Alireza Mahdaviani, Zahra Pourpak, Anna Valerieva, Mariela Vasileva, Tsvetelina Velikova, Elena Petkova, Vasil Dimitrov, Ruggero Di Maulo, on behalf of participating centers, Raz Somech, Hava Golander, Erika J. Sifuentes, Catherine Mansard, Anne Gompel, Bernard Floccard, Claire Blanchard-Delaunay, David Launay, Olivier Fain, Alain Sobel, Stéphane Gayet, Stéphanie Amarger, Guillaume Armengol, Yann Ollivier, Ariane Zélinsky-Gurung, Pierre-Yves Jeandel, Gisèle Kanny, Brigitte Coppéré, Marie Dubrel, Fabien Pelletier, Aurélie Du Thanh, Sébastien Trouiller, Jérôme Laurent, Claire De Moreuil, Christine Audouin Pajot, Alexandre Belot, Ana Rodríguez, Dasha Roa, Alicia Prieto, Maria Luisa Baeza, Borislava Krusheva, Stephanie K. A. Almeida, Rosemeire N. Constantino-Silva, Nyla Melo, Joanna Araujo Simoes, Sandra Mitie U. Palma, Jane da Silva, Bruna F. de Azevedo, Eli Mansour, Teresa González-Quevedo, Carmen Marcos, Teófilo Lobera, Blanca Sáenz de San Pedro, Ernie Avilla, Jacquie Badiou, Karen Binkley, Rozita Borici-Mazi, Linda Howlett, Paul K. Keith, Anne Rowe, Peter Waite, Aurore Billebeau, Isabelle Boccon-Gibbod, Kristina Lis, Yael Laitman, Eitan Friedman, N. M. Gokmen, O. Gulbahar, H. Onay, Z. P. Koc, and A. Z. Sin

Subjects
Immunologic diseases. Allergy, RC581-607
Published
2017
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