roflumilast and Pulmonary-Disease--Chronic-Obstructive

In this paper, we report the discovery of dual M

Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Dose-Response Relationship, Drug; Drug Discovery; Guinea Pigs; Male; Molecular Structure; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Rats; Rats, Inbred BN; Rats, Sprague-Dawley; Receptor, Muscarinic M3; Structure-Activity Relationship

Endogenous nitrosothiols (SNOs) including S-nitrosoglutathione (GSNO) serve as reservoir for bioavailable nitric oxide (NO) and mediate NO-based signaling, inflammatory status and smooth muscle function in the lung. GSNOR inhibition increases pulmonary GSNO and induces bronchodilation while reducing inflammation in lung diseases. In this letter, design, synthesis and structure-activity relationships (SAR) of novel imidazole-biaryl-tetrazole based GSNOR inhibitors are described. Many potent inhibitors (30, 39, 41, 42, 44, 45 and 58) were identified with low nanomolar activity (IC

Topics: Administration, Oral; Aldehyde Oxidoreductases; Animals; Cigarette Smoking; Enzyme Inhibitors; Halogenation; Humans; Imidazoles; Male; Mice; Mice, Inbred C57BL; Pulmonary Disease, Chronic Obstructive; Structure-Activity Relationship; Tetrazoles

A novel class of dual pharmacology bronchodilators targeting both β(2)-adrenoceptor and PDE4 was designed and synthesised by combining the pharmacophores of salmeterol and roflumilast or phthalazinone. All the compounds exhibited better β(2)-adrenoceptor agonist activities (pEC(50)=8.47-9.20) than the reference compound salmeterol (pEC(50)=8.3) and good inhibitory activity on PDE4B2 (IC(50)=0.235-1.093 μM).

Topics: Adrenergic beta-2 Receptor Agonists; Albuterol; Aminopyridines; Benzamides; Bronchodilator Agents; Cyclopropanes; Humans; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Salmeterol Xinafoate

We designed and synthesized a novel class of dual pharmacology bronchodilators targeting both β(2)-adrenoceptor and PDE4 by applying a multivalent approach. The most potent dual pharmacology molecule, compound 29, possessed good inhibitory activity on PDE4B2 (IC(50)=0.278 μM, which was more potent than phthalazinone, IC(50)=0.520 μM) and possessed excellent relaxant effects on tracheal rings precontracted by histamine (pEC(50)=9.3).

Topics: Adrenergic beta-2 Receptor Agonists; Animals; Asthma; Drug Design; Guinea Pigs; Inhibitory Concentration 50; Molecular Structure; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Trachea

A series of pyrido[3',2':4,5]furo[3,2-d]pyrimidines (PFP) were synthesized and tested for phosphodiesterase type 4 (PDE4) inhibitory activity, with the potential to treat asthma and chronic obstructive pulmonary disease (COPD). Structure-activity relationships within this series, leading to an increase of potency on the enzyme, is presented. Both gem-dimethylcyclohexyl moieties fused to the pyridine ring and the substitution at the 5 position of the PFP scaffold, proved to be key elements in order to get a high affinity in the enzyme.

Topics: Animals; Asthma; Caco-2 Cells; Cell Membrane Permeability; Cyclic Nucleotide Phosphodiesterases, Type 4; Ferrets; Humans; Models, Molecular; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Pyrimidines; Structure-Activity Relationship