Novel cyclic compounds as potent phosphodiesterase 4 inhibitors

Article abstract of DOI:10.1021/jm970575f

The synthesis and biological activity of a novel series of 2,2- disubstituted indan-1,3-dione-based PDE4 inhibitors are described. This structurally unique class of PDE4 inhibitors is markedly different from the known PDE4 inhibitors such as RP 73401 (2) and CDP 840 (3). Structure- activity relationship (SAR) studies led to the identification of inhibitors with nanomolar potency and oral activity in a murine endotoxemia model for TNF-α inhibition. Unlike other classical PDE4 inhibitors, several analogues were found to be nonemetic in a canine emesis model at intravenous doses of up to 3 mg/kg.