gsk-256066 and Vomiting

Cyclic nucleotide phosphodiesterase 4 (PDE4) specifically hydrolyzes cyclic adenosine monophosphate (cAMP) and plays vital roles in biological processes such as cancer development. To date, PDE4 inhibitors have been widely studied as therapeutics for the treatment of various diseases such as chronic obstructive pulmonary disease, and many of them have progressed to clinical trials or have been approved as drugs. Herein, we review the advances in the development of PDE4 inhibitors in the past decade and will focus on their pharmacophores, PDE4 subfamily selectivity, and therapeutic potential. Hopefully, this analysis will lead to a strategy for development of novel therapeutics targeting PDE4.

Topics: Animals; Cyclic Nucleotide Phosphodiesterases, Type 4; Drug Development; Drug Discovery; Humans; Molecular Structure; Phosphodiesterase 4 Inhibitors; Protein Conformation; Quinolones; Vomiting

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.

Topics: Administration, Inhalation; Animals; Anti-Inflammatory Agents; Benzamides; Dogs; Ferrets; Humans; Lipopolysaccharides; Lung; Neutrophils; Niacinamide; Phosphodiesterase 4 Inhibitors; Pulmonary Disease, Chronic Obstructive; Rats; Stereoisomerism; Structure-Activity Relationship; Thiazoles; Vomiting