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-hi]indoles: discovery of potent, selective phosphodiesterase type 4 inhibitors.

Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print Cited Medium: Print ISSN: 0022-2623 (Print) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE

Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-

3',5'-Cyclic-AMP Phosphodiesterases/*antagonists & inhibitors ; Anti-Asthmatic Agents/*chemical synthesis ; Anti-Inflammatory Agents, Non-Steroidal/*chemical synthesis ; Azepines/*chemical synthesis ; Indoles/*chemical synthesis ; Niacinamide/*chemical synthesis ; Phosphodiesterase Inhibitors/*chemical synthesis; 3',5'-Cyclic-GMP Phosphodiesterases ; Animals ; Anti-Asthmatic Agents/adverse effects ; Anti-Asthmatic Agents/chemistry ; Anti-Asthmatic Agents/pharmacology ; Anti-Inflammatory Agents, Non-Steroidal/adverse effects ; Anti-Inflammatory Agents, Non-Steroidal/chemistry ; Anti-Inflammatory Agents, Non-Steroidal/pharmacology ; Aorta/enzymology ; Azepines/chemistry ; Azepines/metabolism ; Azepines/pharmacology ; Binding, Competitive ; 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/chemistry ; Indoles/pharmacology ; Isoenzymes/antagonists & inhibitors ; Male ; Monocytes/enzymology ; Niacinamide/analogs & derivatives ; Niacinamide/chemistry ; Niacinamide/metabolism ; Niacinamide/pharmacology ; Ovalbumin/immunology ; Phosphodiesterase I ; Phosphodiesterase Inhibitors/adverse effects ; Phosphodiesterase Inhibitors/chemistry ; Phosphodiesterase Inhibitors/pharmacology ; Phosphoric Diester Hydrolases/metabolism ; Radioligand Assay ; Rats ; Rats, Wistar ; Structure-Activity Relationship ; Trachea/enzymology ; Tumor Necrosis Factor-alpha/biosynthesis ; Vomiting/chemically induced

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 IC(50) values and PDE4 selectivity vs PDE1, -3, and -5. Specifically, one compound (CI-1044, 10e) provided efficient in vitro inhibition of TNFalpha release from hPBMC and hWB with IC(50) values of 0.34 and 0.84 microM, respectively. This compound was found to exhibit potent in vivo activity in antigen-induced eosinophil recruitment in Brown-Norway rats (ED(50) = 3.2 mg/kg po) and in production of TNFalpha in Wistar rats (ED(50) = 2.8 mg/kg po). No emetic side effects at therapeutic doses were observed in ferrets.

0 (Anti-Asthmatic Agents)
0 (Anti-Inflammatory Agents, Non-Steroidal)
0 (Azepines)
0 (Indoles)
0 (Isoenzymes)
0 (Phosphodiesterase Inhibitors)
0 (Tumor Necrosis Factor-alpha)
25X51I8RD4 (Niacinamide)
9006-59-1 (Ovalbumin)
EC 3.1.4.- (Phosphoric Diester Hydrolases)
EC 3.1.4.1 (Phosphodiesterase I)
EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases)
EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 1)
EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 3)
EC 3.1.4.17 (Cyclic Nucleotide Phosphodiesterases, Type 4)
EC 3.1.4.35 (3',5'-Cyclic-GMP Phosphodiesterases)
EC 3.1.4.35 (Cyclic Nucleotide Phosphodiesterases, Type 5)
EC 3.1.4.35 (PDE5A protein, human)
EC 3.1.4.35 (Pde5a protein, rat)
O4T475XIIY (CI 1044)

Date Created: 20001222 Date Completed: 20010118 Latest Revision: 20190710

20231215

10.1021/jm000315p

11123995