Abstract
Oral phosphodiesterase 4 (PDE4) inhibitors, such as cilomilast and roflumilast, have been shown to be efficacious against chronic obstructive pulmonary disease (COPD). However, these drugs have been hampered by mechanism-related side effects such as nausea and emesis at high doses. Compounds administered by inhalation are delivered directly to the site of action and may improve the therapeutic index required to overcome side effects. This paper describes systematic and rational lead optimization to deliver highly potent, long-acting, and efficacious preclinical inhaled PDE4 inhibitors with low emetic potential.
MeSH terms
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Administration, Inhalation
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Animals
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Anti-Inflammatory Agents / adverse effects
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Anti-Inflammatory Agents / chemical synthesis*
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Anti-Inflammatory Agents / pharmacology
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Benzamides / adverse effects
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Benzamides / chemical synthesis*
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Benzamides / pharmacology
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Dogs
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Ferrets
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Humans
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Lipopolysaccharides / pharmacology
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Lung / drug effects
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Lung / immunology
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Lung / pathology
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Neutrophils / pathology
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Niacinamide / adverse effects
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Niacinamide / analogs & derivatives*
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Niacinamide / chemical synthesis
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Niacinamide / pharmacology
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Phosphodiesterase 4 Inhibitors / adverse effects
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Phosphodiesterase 4 Inhibitors / chemical synthesis*
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Phosphodiesterase 4 Inhibitors / pharmacology
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Pulmonary Disease, Chronic Obstructive / drug therapy*
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Rats
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Stereoisomerism
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Structure-Activity Relationship
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Thiazoles / adverse effects
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Thiazoles / chemical synthesis*
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Thiazoles / pharmacology
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Vomiting / chemically induced*
Substances
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2-(4'-((3,5-dimethylpiperazin-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fluoro-N-(4-(2-hydroxy-5-methylbenzamido)cyclohexyl)nicotinamide
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Anti-Inflammatory Agents
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Benzamides
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Lipopolysaccharides
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N-(4-(2-(4'-((3,5-dimethylpiperazin-1-yl)methyl)-2'-(morpholinomethyl)biphenyl-3-yloxy)-5-fluoronicotinamido)cyclohexyl)-4-methylthiazole-2-carboxamide
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Phosphodiesterase 4 Inhibitors
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Thiazoles
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Niacinamide