2. Academic Validation
  3. 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

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

  • J Med Chem. 2000 Dec 14;43(25):4850-67. doi: 10.1021/jm000315p.
C Burnouf 1,  E Auclair,  N Avenel,  B Bertin,  C Bigot,  A Calvet,  K Chan,  C Durand,  V Fasquelle,  F Féru,  R Gilbertsen,  H Jacobelli,  A Kebsi,  E Lallier,  J Maignel,  B Martin,  S Milano,  M Ouagued,  Y Pascal,  M P Pruniaux,  J Puaud,  M N Rocher,  C Terrasse,  R Wrigglesworth,  A M Doherty
Affiliations

Affiliation

  • 1 Pfizer Global Research & Development, Fresnes Laboratories, 3 à 9 rue de la Loge, 94265 Fresnes, France. catherine.burnouf@pfizer.com
PMID: 11123995 DOI: 10.1021/jm000315p
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.

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