Synthesis, Structure−Activity Relationships, and Pharmacological Profile of 9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-h i]indoles: Discovery of Potent, Selective Phosphodiesterase Type 4 Inhibitors

The synthesis, structure−activity relationships, and biological properties of a novel series of potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC50 values and PDE4 selectivity vs PDE1,...

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Published in:	Journal of medicinal chemistry Vol. 43; no. 25; pp. 4850 - 4867
Main Authors:	Burnouf, Catherine, Auclair, Eric, Avenel, Nadine, Bertin, Bernadette, Bigot, Christèle, Calvet, Alain, Chan, Kam, Durand, Corinne, Fasquelle, Veronique, Féru, Frédéric, Gilbertsen, Richard, Jacobelli, Henry, Kebsi, Adel, Lallier, Emmanuelle, Maignel, Jacquie, Martin, Brigitte, Milano, Stéphane, Ouagued, Malika, Pascal, Yves, Pruniaux, Marie-Pierre, Puaud, Jocelyne, Rocher, Marie-Noëlle, Terrasse, Christophe, Wrigglesworth, Roger, Doherty, Annette M
Format:	Journal Article
Language:	English
Published:	Washington, DC American Chemical Society 14-12-2000
Subjects:	3',5'-Cyclic-AMP Phosphodiesterases - antagonists & inhibitors 3',5'-Cyclic-GMP Phosphodiesterases Animals Anti-Asthmatic Agents - adverse effects Anti-Asthmatic Agents - chemical synthesis Anti-Asthmatic Agents - chemistry Anti-Asthmatic Agents - pharmacology Anti-Inflammatory Agents, Non-Steroidal - adverse effects Anti-Inflammatory Agents, Non-Steroidal - chemical synthesis Anti-Inflammatory Agents, Non-Steroidal - chemistry Anti-Inflammatory Agents, Non-Steroidal - pharmacology Aorta - enzymology Azepines - chemical synthesis Azepines - chemistry Azepines - metabolism Azepines - pharmacology Binding, Competitive Biological and medical sciences Bones, joints and connective tissue. Antiinflammatory agents Brain - metabolism Bronchoalveolar Lavage Cell Line Cyclic Nucleotide Phosphodiesterases, Type 1 Cyclic Nucleotide Phosphodiesterases, Type 3 Cyclic Nucleotide Phosphodiesterases, Type 4 Cyclic Nucleotide Phosphodiesterases, Type 5 Dogs Eosinophils - pathology Ferrets Guinea Pigs Humans In Vitro Techniques Indoles - adverse effects Indoles - chemical synthesis Indoles - chemistry Indoles - pharmacology Isoenzymes - antagonists & inhibitors Male Medical sciences Monocytes - enzymology Niacinamide - analogs & derivatives Niacinamide - chemical synthesis Niacinamide - chemistry Niacinamide - metabolism Niacinamide - pharmacology Ovalbumin - immunology Pharmacology. Drug treatments Phosphodiesterase I Phosphodiesterase Inhibitors - adverse effects Phosphodiesterase Inhibitors - chemical synthesis Phosphodiesterase Inhibitors - chemistry Phosphodiesterase Inhibitors - pharmacology Phosphoric Diester Hydrolases - metabolism Radioligand Assay Rats Rats, Wistar Respiratory system Structure-Activity Relationship Trachea - enzymology Tumor Necrosis Factor-alpha - biosynthesis Vomiting - chemically induced Allergy Angular nitrogen heterocycle Isozyme Lactam Esterases Selectivity Phosphoric diester hydrolases Antiasthma agent Pyridine derivatives Structure activity relation Aromatic compound Obstructive pulmonary disease Inhibition Chemical synthesis Tumor necrosis factor α Human 3',5'-Cyclic-nucleotide phosphodiesterase Monocyte Respiratory disease Enzyme Antiinflammatory agent Benzene derivatives Cytokine Oral administration Enzyme inhibitor Tricyclic compound Asthma Immunomodulator In vivo Chemotherapy Experimental disease Treatment Animal Hydrolases Carboxamide Immunosuppressive agent
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Summary:	The synthesis, structure−activity relationships, and biological properties of a novel series of potent and selective phosphodiesterase type 4 (PDE4) inhibitors are described. These new aminodiazepinoindoles displayed in vitro PDE4 activity with submicromolar IC50 values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNFα release from hPBMC and hWB with IC50 values of 0.34 and 0.84 μM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED50 = 3.2 mg/kg po) and in production of TNFα in Wistar rats (ED50 = 2.8 mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.
Bibliography:	istex:46C7E36EE715D8892EBAD4C1B64F540082271089 ark:/67375/TPS-Q1PLZG9M-L
ISSN:	0022-2623 1520-4804
DOI:	10.1021/jm000315p