ABSTRACT
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.
Subject(s)
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 inducedABSTRACT
Litchi chinensis (Sapindaceae) is a tree that originates from China and is cultivated for its sweet fruits all over the world in warm climates. Unusual fatty acids such as cyclopropanoic fatty acids have been identified in the seeds of Litchi. Because of their potential value for industry (as inks, cosmetics, detergents, lubricants, etc.), the variability in the relative levels of unusual fatty acids in the seeds of 28 different Litchi varieties was analysed at two locations (on Réunion Island in the Indian Ocean) and on two different harvest dates. Except for one variety, all the seeds contained cis-9,10-methylene-octadecanoic acid (C(19)CA) at a relative level of 35-48%. The only variety that contained no or only traces of C(19)CA was Groff, seeds of which were significantly much smaller than those from all other varieties.
