Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0042963 (vomiting)
 31,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Phosphodiesterase-4 (PDE4), one of eleven PDE enzyme families, specifically catalyzes hydrolysis of cyclic AMP (cAMP); it has four subtypes (PDE4A-D) with at least 25 splice variants. PDE4 plays a critical role in the control of intracellular cAMP concentrations. PDE4 inhibitors produce antidepressant actions in both animals and humans via enhancement of cAMP signaling in the brain. However, their clinical utility has been hampered by side effects, in particular nausea and emesis. While there is still a long way to go before PDE4 inhibitors with high therapeutic indices are available for treatment of depressive disorders, important advances have been made in the development of PDE4 inhibitors as antidepressants. First, limited, but significant studies point to PDE4D as the major PDE4 subtype responsible for antidepressant-like effects of PDE4 inhibitors, although the role of PDE4A cannot be excluded. Second, PDE4D may contribute to emesis, the major side effect of PDE4 inhibitors. For this reason, identification of roles of PDE4D splice variants in mediating antidepressant activity is particularly important. Recent studies using small interfering RNAs (siRNAs) have demonstrated the feasibility to identify cellular functions of individual PDE4 variants. Third, mixed inhibitors of PDE4 and PDE7 or PDE4 and serotonin reuptake have been developed and may be potential antidepressants with minimized side effects. Finally, relatively selective inhibitors of one or two PDE4 subtypes have been synthesized using structure- and scaffold-based design. This review also discusses the relationship between PDE4 and antidepressant activity based on structures, brain distributions, and pharmacological properties of PDE4 and its isoforms.
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PMID:Cyclic AMP-specific phosphodiesterase-4 as a target for the development of antidepressant drugs. 1944 82

Phosphodiesterase 4 (PDE4) belongs to a family of enzymes which catalyzes the breakdown of 3, 5'-adenosine cyclic monophosphate (cAMP) and is ubiquitously expressed in inflammatory cells. There is little evidence that inflammatory diseases are caused by increased expression of this isoenzyme, although human inflammatory cell activity can be suppressed by selective PDE4 inhibitors. Consequently, there is intense interest in the development of selective PDE4 inhibitors for the treatment of a range of inflammatory diseases, including asthma, chronic obstructive pulmonary disease (COPD), inflammatory bowel disease, and psoriasis. Recent clinical trials with roflumilast in COPD have confirmed the therapeutic potential of targeting PDE4 and recently roflumilast has been approved for marketing in Europe and the USA, although side effects such as gastrointestinal disturbances, particularly nausea and emesis as well as headache and weight loss, may limit the use of this drug class, at least when administered by the oral route. However, a number of strategies are currently being pursued in attempts to improve clinical efficacy and reduce side effects of PDE4 inhibitors, including delivery via the inhaled route, development of nonemetic PDE4 inhibitors, mixed PDE inhibitors, and/or antisense biologicals targeted toward PDE4.
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PMID:Phosphodiesterase inhibitors in the treatment of inflammatory diseases. 2169 50

Phosphodiesterase-4 (PDE-4) is responsible for metabolizing adenosine 3',5'-cyclic monophosphate that reduces the activation of a wide range of inflammatory cells including eosinophils. PDE-4 inhibitors are under development for the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease. Herein, we report a novel PDE-4 inhibitor, PDE-423 (3-[1-(3-cyclopropylmethoxy-4-difluoromethoxybenzyl)-1H-pyrazol-3-yl]-benzoic acid), which shows good in vitro and in vivo oral activities. PDE-423 exhibited in vitro IC(50)s of 140 nM and 550 nM in enzyme assay and cell-based assay, respectively. In vivo study using ovalbumin-induced asthmatic mice revealed that PDE-423 reduced methacholine-stimulated airway hyperreactivity in a dose-dependent manner by once daily oral administration (ED(50)=18.3 mg/kg), in parallel with decreased eosinophil peroxidase activity and improved lung histology. In addition, PDE-423 was effective in diminishing lipopolysaccharide-induced neutrophilia in vivo as well as in vitro. Oral administration of PDE-423 (100 mg/kg) had no effect on the duration of xylazine/ketamine-induced anesthesia and did not induce vomiting incidence in ferrets up to the dose of 1000 mg/kg. The present study indicates that a novel PDE-4 inhibitor, PDE-423, has good pharmacological profiles implicating this as a potential candidate for the development of a new anti-asthmatic drug.
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PMID:Discovery of a novel orally active PDE-4 inhibitor effective in an ovalbumin-induced asthma murine model. 2255 69


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