Abstract
PurposeThis 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.MethodsInhibition 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.ResultsGRMS-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 IC50 of 1.06 and 0.26 mg/L, while (±)-LSF with IC50 of 5.80 and 1.06 mg/L, respectively. Moreover, GRMS-55 significantly ameliorated symptoms of ConA-induced hepatitis.ConclusionsPDE4B 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.
Highlights
Phosphodiesterases (PDEs) are enzymes that hydrolyze the second messengers – 3′,5′-cyclic adenosine monophosphate and 3′,5′-cyclic guanosine monophosphate
The reference compounds, being selective or preferential inhibitors of individual isoenzymes, exhibited micromolar activity, while papaverine and milrinone demonstrated IC50 values below 1 μM on hrPDE10A and hrPDE3A, respectively. Both GRMS-55 and (±)-LSF demonstrated an inhibitory activity against hrPDE4B, which is crucial for achieving the antiinflammatory and immunomodulatory effects [1]
We demonstrated that PDE4B but not PDE4D blockage is essential to obtain a therapeutic effect in animal models of immune-mediated hepatitis, autoimmune rheumatoid arthritis, and endotoxemia
Summary
Phosphodiesterases (PDEs) are enzymes that hydrolyze the second messengers – 3′,5′-cyclic adenosine monophosphate (cAMP) and 3′,5′-cyclic guanosine monophosphate (cGMP). Eleven types of this enzyme have been described to date. It is well known that T cells and increased levels of cytokines, such as TNF-α are involved in the development of these conditions that include, among the others, rheumatoid arthritis (RA), autoimmune hepatitis (AIH), or sepsis. These enzymes by affecting cAMP levels contribute to the regulation of immune response with respect to cytokine/chemokine production and control lymphocyte proliferation. The results of some pre-clinical studies indicate that an inhibition of PDE4B subtype is mainly engaged in the antiinflammatory activity of selective PDE4 inhibitors [1,14], while a PDE4D blockage leads to the undesirable effects, such as nausea and emesis [15]
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