The phosphodiesterases (PDEs) are responsible for the hydrolysis of intracellular cyclic adenosine and guanosine monophosphate (cAMP and cGMP, respectively). They are classified into 11 major families (PDE1-11) and the type 4 phosphodiesterase (PDE4) is a cAMP-specific enzyme localized in airway smooth muscle cells as well as in immune and inflammatory cells. The PDE4 activity is associated with a wide variety of diseases some of which have been related to an inflammatory state, (e.g. asthma, chronic obstructive pulmonary disease (COPD), rheumatoid arthritis (RA)) while others have recently been connected to autoimmune pathology. Therefore, an intense effort toward the development of PDE4 inhibitors has been generated for the last decade. Unfortunately, the effects of prototype PDE4 inhibitors have been compromised by side effects such as nausea and emesis and the clinical use of those compounds is still limited. Several companies have focused on the design of a new generation of PDE4 inhibitors dissociating beneficial activity and adverse effects. This review highlights the recent data of the most advanced clinical candidates, the design and structure activity relationships of the recent structural series reported in the literature over the last two years, as well as recent advances in the multiple therapeutic indications of PDE4 inhibitors (a review with 375 references).

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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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