Smithkline Beecham Corporation

Theodore J Torphy

Siegfried B Christensen, Iv

George P Livi

Mary S Barnette

Megan McHale McLaughlin

Richard Nieman

Anthony S Rebuck

This invention relates to a method for the prophylaxis of or for treating COPD by administering a PDE4 inhibitor which has a defined therapeutic ratio.

Method for treating COPD

Methods of treating exercise-induced asthma using a PDE-4 inhibitor are disclosed.

Method for treating exercise induced asthma

This invention relates to treating pulmonary diseases such as chronic obstructive pulmonary disease or asthma by administering a phosphodiesterase 4 inhibitor in combination with beta adrenergic bronchodilator.

Therapies for treating pulmonary diseases

Human brain phosphodiesterase

This invention relates to treating pulmonary diseases such as chronic obstructive pulmonary disease or asthma by administering a phosphodiesterase-4 inhibitor with a beta-adrenergic bronchodilator.

Isolated cDNA clones from human brain (frontal cortex) cDNA libraries that encode a unique subtype of the low K.sub.m, cAMP-specific phosphodiesterases (PDE IVs) are disclosed. Analysis of the distribution of hPDE IV.sub.B mRNA expression in various human tissues using a nonconserved fragment of the cDNA as a probe revealed a restricted pattern of expression, with an .about.4-kb mRNA detected in brain, heart, lung and skeletal muscle and not in placenta, liver, kidney or pancreas. Furthermore, an additional .about.5-kb hPDE IV.sub.B.sup.- related mRNA species was detected in brain tissue. Expression of hPDE IV.sub.B in a genetically-engineered PDE-deficient strain of the yeast Saccharomyces cerevisiae resulted in the overproduction of cAMP PDE activity which displayed the expected kinetic characteristics for a PDE IV: 1) low K.sub.m (4.3 .mu.M) for cAMP, 2) high K.sub.m (&gt;3 mM) for cGMP, and 3) sensitivity to rolipram (K.sub.i =0.085 .mu.M), a selective inhibitor of PDE IV. Recombinant hPDE IV.sub.B also bound [.sup.3 H] R-rolipram saturably and with a high affinity. Analysis of [.sup.3 H] R-rolipram binding data revealed curvilinear Scatchard plots, suggesting the presence of two non-interacting high affinity rolipram binding sites (K.sub.d =0.4 and 6 nM) or a negatively cooperative interaction among multiple binding sites. This novel enzyme is particularly useful for screening candidate compounds for their ability to serve as potential anti-depressant, antiasthmatic or anti-inflammatory agents.

This invention relates to a method for selecting PDE IV inhibitors which have a salutory therapeutic index, and to compounds having these properties.

Anti-inflammatory and anti-asthma treatment with reduced side effects

Compounds and methods for treating PDE IV-related diseases

Isolated cDNA clones from human brain (frontal cortex) cDNA libraries that encode a unique subtype of the low K.sub.m, cAMP-specific phosphodiesterases (PDE IVs) are disclosed. Analysis of the distribution of hPDE IV.sub.B mRNA expression in various human tissues using a nonconserved fragment of the cDNA as a probe revealed a restricted pattern of expression, with an .about.4-kb MRNA detected in brain, heart, lung and skeletal muscle and not in placenta, liver, kidney or pancreas. Furthermore, an additional .about.5-kb hPDE IV.sub.B.sup.- related mRNA species was detected in brain tissue. Expression of hPDE IV.sub.B in a genetically-engineered PDE-deficient strain of the yeast Saccharomyces cerevisiae resulted in the overproduction of cAMP PDE activity which displayed the expected kinetic characteristics for a PDE IV: 1) low K.sub.m (4.3 .mu.M) for cAMP, 2) high K.sub.m (&gt;3 mM) for cGMP, and 3) sensitivity to rolipram (K.sub.i =0.085 .mu.M), a selective inhibitor of PDE IV. Recombinant HPDE IV.sub.B also bound �.sup.3 H!R-rolipram saturably and with a high affinity. Analysis of �.sup.3 H!R-rolipram binding data revealed curvilinear Scatchard plots, suggesting the presence of two non-interacting high affinity rolipram binding sites (K.sub.d =0.4 and 6 nM) or a negatively cooperative interaction among multiple binding sites. This novel enzyme is particularly useful for screening candidate compounds for their ability to serve as potential anti-depressant, antiasthmatic or anti-inflammatory agents.

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Bryn Mawr, PA, United States of America

Theodore J Torphy