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Purpose  This study aimed to assess the activity of two phosphodiesterase (PDE) inhibitors, namely GRMS-55 and racemic lisofylline ((±)-LSF))  in vitro  and in animal models of immune-mediated disorders.    Methods  Inhibition of human recombinant (hr)PDEs and TNF-alpha release from LPS-stimulated whole rat blood by the studied compounds were assessed  in vitro . LPS-induced endotoxemia, concanavalin A (ConA)-induced hepatitis, and collagen-induced arthritis (CIA) animal models were used for  in vivo  evaluation. The potency of the investigated compounds was evaluated using PK/PD and PK/PD/disease progression modeling.    Results  GRMS-55 is a potent hrPDE7A and hrPDE1B inhibitor, while (±)-LSF most strongly inhibits hrPDE3A and hrPDE4B. GRMS-55 decreased TNF-alpha levels  in vivo  and CIA progression with  IC   50   of 1.06 and 0.26 mg/L, while (±)-LSF with  IC   50   of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis.    Conclusions  PDE4B but not PDE4D inhibition appears to be mainly engaged in anti-inflammatory activity of the studied compounds. GRMS-55 and (±)-LSF seem to be promising candidates for future studies on the treatment of immune-related diseases. The developed PK/PD models may be used to assess the anti-inflammatory and anti-arthritic potency of new compounds for the treatment of rheumatoid arthritis and other inflammatory disorders.    Electronic supplementary material  The online version of this article (10.1007/s11095-019-2727-z) contains supplementary material, which is available to authorized users.

Comparative Assessment of the New PDE7 Inhibitor – GRMS-55 and Lisofylline in Animal Models of Immune-Related Disorders: A PK/PD Modeling Approach