Allen J Duplantier | PubMed Health

PubMed2007

SAR of a series of 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridines as potent inhibitors of human eosinophil phosphodiesterase.

The potency and physical properties of a previously reported 7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine series of human eosinophil phosphodiesterase inhibitors were improved by tying the lactam moiety into a triazolo ring. The resulting 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine series provided nonionizable analogs with melting point properties suitable for micronization. Substitution at the 3-position of the 5,6-dihydro-(9H)-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-alpha]pyridine tricycle led to a 2-thienyl analog, 19 (tofimilast), a potent PDE4 inhibitor with low oral bioavailability and no emesis-associated behaviors in ferrets at plasma concentrations up to 152 ng/mL.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2006

Galanin function in the central nervous system.

The peptide galanin is primarily expressed in the central nervous system (CNS) and it is active in a range of models of behavior. The identification of three galanin receptors, whose distribution of expression is distinct but overlapping, is evidence of the complexity of galanin's regulation of neuronal function. The majority of studies examining galanin have used broad methods to identify its function, employing nonselective peptide agonists and antagonists, or transgenic animal models. While these studies were informative, they provided limited insight to the specific receptors mediating the effects of galanin. The recent identification of potent, brain-permeable and selective galanin antagonists suggests it will be possible to gain greater insight into the function of each galanin receptor and their potential as therapeutic targets. This article reviews the roles identified for galanin in the CNS and how ligands of the galanin receptors, both peptidic and small-molecule, have been used to explore the behavioral models that characterize these roles.

Alzheimer Disease↗