Type 4 phosphodiesterase inhibitors and their potential in the treatment of inflammatory disease

Brito, FB de; Souness, J E; Warne, P.J.

doi:10.1517/14728214.2.1.249

Cited by 20 publications

(5 citation statements)

References 29 publications

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“…Large numbers of compounds of diverse structures have been synthesized which are believed to exert their anti‐inflammatory effects through inhibition of PDE4 (Palfreyman & Souness, 1996; De Brito et al , 1997). However, in some instances, poor correlations have been obtained between PDE4 inhibition and functional responses (Harris et al , 1989; Souness et al , 1991).…”

Section: Introductionmentioning

confidence: 99%

Evidence that cyclic AMP phosphodiesterase inhibitors suppress interleukin‐2 release from murine splenocytes by interacting with a ‘low‐affinity’ phosphodiesterase 4 conformer

Souness¹,

Houghton

Sardar³

et al. 1997

British J Pharmacology

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1 We have investigated the suppressive e ects of rolipram, RP 73401 (piclamilast) and other structurally diverse inhibitors of cyclic AMP-speci®c phosphodiesterase 4 (PDE4) on interleukin (IL)-2 generation from Balb/c mouse splenocytes exposed to the superantigen, Staphylococcocal enterotoxin-A (Staph. A). The purpose was to determine whether their potencies are more closely correlated with inhibition of PDE4 from CTLL cells, against which rolipram displays weak potency (low-a nity PDE4), or displacement of [ 3 H]-(+)-rolipram from its high-a nity binding site (HARBS) in mouse brain cytosol. 2 RP 73401 (IC 50 0.46+0.07 nM, n=4) was a very potent inhibitor of Staph. A-induced IL-2 release from Balb/c mouse splenocytes, being 41100 fold more potent than (+)-rolipram (IC 50 540+67 nM, n=3). 3 A close correlation (r=0.95) was observed between suppression of IL-2 release by PDE inhibitors and inhibition of PDE4. In contrast, little correlation (r=0.39) was observed between suppression of IL-2 release and their a nities for the high-a nity rolipram binding site (HARBS). 4 RP 73401 only inhibited partially (30 ± 40%) Staph. A-induced incorporation of [ 3 H]-thymidine into splenocyte DNA. The PDE3 inhibitor, siguazodan (10 mM), had little or no e ect on IL-2 release or DNA synthesis. This concentration of siguazodan did not enhance the inhibitory action of RP 73401 on IL-2 release but potentiated its e ect on DNA synthesis, increasing potency and e cacy. 5 Staph. A-induced DNA synthesis was only partially inhibited by anti-IL-2 neutralizing antibody, whereas dexamethazone (100 nM) and cyclosporine A (100 nM) completely blocked the response. 6 RP 73401 (IC 50 6.3+1.9 nM, n=4) was 140 fold more potent than rolipram (IC 50 900+300 nM, n=3) in inhibiting Staph. A-induced [ 3 H]-thymidine incorporation into splenocyte DNA. 7 The results implicate a low-a nity form of PDE4 in the suppression of Staph. A-induced IL-2 release from murine splenocytes by PDE inhibitors. The data also indicate that mitogenic factors other than IL-2, whose elaboration or responses to which are regulated by PDE3 as well as PDE4, contribute to the superantigen-induced DNA synthesis.

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Section: Introductionmentioning

confidence: 99%

Evidence that cyclic AMP phosphodiesterase inhibitors suppress interleukin‐2 release from murine splenocytes by interacting with a ‘low‐affinity’ phosphodiesterase 4 conformer

Souness¹,

Houghton

Sardar³

et al. 1997

British J Pharmacology

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“…Analogues of thalidomide have been reported to possibly enhance tumor necrosis factor alpha (TNF) inhibitory activity (Corral et al, 1996;Muller et al, 1996) and phosphodiesterase type 4 (PD4) inhibition (Muller et al, 1998), hence showing potential for the treatment of inflammatory diseases (de Brito et al, 1997). Among these substances are phenethylsulfones substituted in the position to the phenyl group with a 1-oxoisoindoline or 1,3-dioxoisoindoline group that can reduce the levels of TNF in a mammal.…”

Section: Chemical Contextmentioning

confidence: 99%

Crystal structure of an apremilast ethanol hemisolvate hemihydrate solvatomorph

Wu¹,

Liu²,

Xu³

et al. 2017

Acta Cryst E

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“…The PDE4 gene family and subfamilies show characteristic cAMP substrate specificity and high affinity, and inhibitors such as rolipram, roflumilast, and ariflo are relatively selective inhibitors of PDE4 isoforms. These inhibitors have reached the clinic as anti‐inflammatory drugs for asthma and COPD 1, 2 and are being studied as therapeutic agents for such diverse diseases as rheumatoid arthritis, multiple sclerosis, type II diabetes, and autoimmune diseases 3, 4.…”

Section: Introductionmentioning

confidence: 99%

Molecular modeling study of binding to the catalytic site of PDE4 enzymes by a novel class of inhibitors

Lawrenz

Salter

Wierzbicki

et al. 2005

Int J of Quantum Chemistry

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Cyclic nucleotide phosphodiesterases (PDEs) comprise a superfamily of enzymes that hydrolyze the second messengers adenosine and guanosine 3Ј,5Ј-cyclic monophosphate (cAMP and cGMP) to their noncyclic nucleotides (5Ј-AMP and 5Ј-GMP). Selective inhibitors of all 11 gene families of PDEs are being sought based on the different biochemical properties of the different isoforms, including their substrate specificities. The PDE4 gene family consists of cAMP-specific isoforms; selective PDE4 inhibitors such as rolipram have been developed, and related agents are used clinically as anti-inflammatory agents for asthma and COPD. The known crystal structures of PDE4 bound with rolipram and IBMX have allowed us to define plausible binding orientations for a novel class of benzylpyridazinone-based PDE4 inhibitors represented by EMD 94360 and EMD 95832 that are structurally distinct from rolipram. Molecular mechanics modeling with autodocking is used to explore energetically favorable binding orientations within the PDE4 catalytic site. We present two putative orientations for EMD 94360/95832 inhibitor binding. Our estimated interaction energies for rolipram, IBMX, EMD 94360, and EMD 95832 are consistent with the experimental data for their IC 50 values. Key binding residues and interactions in these orientations are identified and compared with known binding motifs proposed for rolipram. The experimentally observed improved strength of inhibition exhibited by this novel class of PDE4 inhibitors is explained by the molecular modeling reported here.

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Type 4 phosphodiesterase inhibitors and their potential in the treatment of inflammatory disease

Cited by 20 publications

References 29 publications

Evidence that cyclic AMP phosphodiesterase inhibitors suppress interleukin‐2 release from murine splenocytes by interacting with a ‘low‐affinity’ phosphodiesterase 4 conformer

Evidence that cyclic AMP phosphodiesterase inhibitors suppress interleukin‐2 release from murine splenocytes by interacting with a ‘low‐affinity’ phosphodiesterase 4 conformer

Crystal structure of an apremilast ethanol hemisolvate hemihydrate solvatomorph

Molecular modeling study of binding to the catalytic site of PDE4 enzymes by a novel class of inhibitors

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