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

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 vitr o 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 TNF alpha release from hPBMC and; hWB with IC50:valu es of 0.34 and 0.84 muM, respectively. This compound was found to exhibit p otent in vivo activity in antigen-induced eosinophil recruitment in Brown-N orway rats (ED50 = 3.2 mg/kg po) and in production of TNF alpha in Wistar f ats (ED50 = 2.8; mg/kg po). No emetic side effects at therapeutic doses wer e observed in ferrets.