roflumilast 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

Topics: Aminopyridines; Animals; Benzamides; Cyclic Nucleotide Phosphodiesterases, Type 4; Cyclopropanes; Dementia, Vascular; Dogs; Drug Design; Humans; Male; Mice, Inbred C57BL; Molecular Structure; Phosphodiesterase 4 Inhibitors; Protein Binding; Rolipram; Structure-Activity Relationship; Vomiting; Xanthones

A forward chemical genetic approach was followed to discover new targets and lead compounds for Parkinson's disease (PD) treatment. By analysis of the cell protection produced by some small molecules, a diphenyl sulfide compound was revealed to be a new phosphodiesterase 7 (PDE7) inhibitor and identified as a new hit. This result allows us to confirm the utility of PDE7 inhibitors as a potential pharmacological treatment of PD. On the basis of these data, a diverse family of diphenyl sulfides has been developed and pharmacologically evaluated in the present work. Moreover, to gain insight into the safety of PDE7 inhibitors for human chronic treatment, we evaluated the new compounds in a surrogate emesis model, showing nonemetic effects.

Topics: Anesthesia; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood-Brain Barrier; Cell Survival; Chemistry Techniques, Synthetic; Cyclic Nucleotide Phosphodiesterases, Type 7; Drug Evaluation, Preclinical; Humans; Inhibitory Concentration 50; Male; Mice, Inbred Strains; Models, Molecular; Phosphodiesterase Inhibitors; Rats; Structure-Activity Relationship; Sulfides; Vomiting

The solubility-driven optimization of a series of 1,7-napthyridine phosphodiesterase-4 inhibitors is described. Directed structural changes resulted in increased aqueous solubility, enabling superior pharmacokinetic properties with retention of PDE4 inhibition. A range of potent and orally bioavailable compounds with good in vivo efficacy in animal models of inflammation and reduced emetic potential compared to previously described drugs were synthesized. Compound 2d was taken forward as a clinical candidate for the treatment of COPD.

Topics: Animals; Cells, Cultured; Disease Models, Animal; Drug Design; Drug Evaluation, Preclinical; Humans; Magnetic Resonance Spectroscopy; Mice; Models, Molecular; Phosphodiesterase 4 Inhibitors; Rats; Solubility; Vomiting

Phosphodiesterase 4 (PDE4), the primary cAMP-hydrolyzing enzyme in cells, is a promising drug target for a wide range of conditions. Here we present seven co-crystal structures of PDE4 and bound inhibitors that show the regulatory domain closed across the active site, thereby revealing the structural basis of PDE4 regulation. This structural insight, together with supporting mutagenesis and kinetic studies, allowed us to design small-molecule allosteric modulators of PDE4D that do not completely inhibit enzymatic activity (I(max) approximately 80-90%). These allosteric modulators have reduced potential to cause emesis, a dose-limiting side effect of existing active site-directed PDE4 inhibitors, while maintaining biological activity in cellular and in vivo models. Our results may facilitate the design of CNS therapeutics modulating cAMP signaling for the treatment of Alzheimer's disease, Huntington's disease, schizophrenia and depression, where brain distribution is desired for therapeutic benefit.

Topics: Allosteric Regulation; Amino Acid Sequence; Animals; Behavior, Animal; Benzhydryl Compounds; Biological Assay; Catalytic Domain; Cell Line; Cognition; Crystallography, X-Ray; Cyclic Nucleotide Phosphodiesterases, Type 4; Disease Models, Animal; Drug Design; Humans; Kinetics; Mice; Models, Molecular; Molecular Sequence Data; Phenylurea Compounds; Phosphodiesterase 4 Inhibitors; Phosphodiesterase Inhibitors; Protein Structure, Tertiary; Structure-Activity Relationship; Vomiting