3 research outputs found
Discovery of 3,4-Dihydropyrimidin-2(1<i>H</i>)‑ones As a Novel Class of Potent and Selective A<sub>2B</sub> Adenosine Receptor Antagonists
We
describe the discovery and optimization of 3,4-dihydropyrimidin-2(1<i>H</i>)-ones as a novel family of (nonxanthine) A<sub>2B</sub> receptor antagonists that exhibit an unusually high selectivity
profile. The Biginelli-based hit optimization process enabled a thoughtful
exploration of the structure–activity and structure–selectivity
relationships for this chemotype, enabling the identification of ligands
that combine structural simplicity with excellent hA<sub>2B</sub> AdoR
affinity and remarkable selectivity profiles
Modulation of cAMP-Specific PDE without Emetogenic Activity: New Sulfide-Like PDE7 Inhibitors
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
Effect of Phosphodiesterase 7 (PDE7) Inhibitors in Experimental Autoimmune Encephalomyelitis Mice. Discovery of a New Chemically Diverse Family of Compounds
Phosphodiesterase (PDE) 7 is involved in proinflammatory
processes, being widely expressed both on lymphocytes and on certain
brain regions. Specific inhibitors of PDE7 have been recently reported
as potential new drugs for the treatment of neurological disorders
because of their ability to increase intracellular levels of cAMP
and thus to modulate the inflammatory process, as a neuroprotective
well-established strategy. Multiple sclerosis is an unmet disease
in which pathologies on the immune system, T-cells, and specific neural cells are involved
simultaneously. Therefore, PDE7 inhibitors able to interfere with
all these targets may represent an innovative therapy for this pathology.
Here, we report a new chemically diverse family of heterocyclic PDE7
inhibitors, discovered and optimized by using molecular modeling studies,
able to increase cAMP levels in cells, decrease inflammatory activation
on primary neural cultures, and also attenuate the clinical symptoms
in the experimental autoimmune encephalomyelitis (EAE) mouse model.
These results led us to propose the use of PDE7 inhibitors as innovative
therapeutic agents for the treatment of multiple sclerosis