RESUMO
Phosphodiesterase 11A4 (PDE11A4) is a dual-acting cyclic nucleotide hydrolase expressed in neurons in the CA1, subiculum, amygdalostriatal transition area and amygdalohippocampal area of the extended hippocampal formation. PDE11A4 is the only PDE enzyme to emanate solely from hippocampal formation, a key brain region for the formation of long-term memory. PDE11A4 expression increases in the hippocampal formation of both humans and rodents as they age. Interestingly, PDE11A knockout mice do not show age-related deficits in associative memory and show no gross histopathology. This suggests that inhibition of PDE11A4 might serve as a therapeutic option for age-related cognitive decline. A novel, yeast-based high throughput screen previously identified moderately potent, selective PDE11A4 inhibitors, and this work describes initial efforts that improved potency more than 10-fold and improved some pharmaceutical properties of one of these scaffolds, leading to selective, cell-penetrant PDE11A4 inhibitors, one of which is 10-fold more potent compared to tadalafil in cell-based activity.
Assuntos
Disfunção Cognitiva , Inibidores de Fosfodiesterase , Humanos , Animais , Camundongos , Inibidores de Fosfodiesterase/farmacologia , Inibidores de Fosfodiesterase/uso terapêutico , Inibidores de Fosfodiesterase/metabolismo , 3',5'-GMP Cíclico Fosfodiesterases/metabolismo , Diester Fosfórico Hidrolases/metabolismo , Encéfalo/metabolismo , Camundongos Knockout , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismoRESUMO
A new carbon(0) complexâ 2 with two different L ligands, a phosphine and a sulfoxide, was synthesized and fully characterized. This new type of carbone exhibits excellent coordination ability, in contrast to the related phosphine/sulfide-supported carbon(0) complexes. Several organometallic complexes were isolated and, of special interest, the νav (CO) value of RhI -dicarbonyl complex indicates that 2 has a donor capability superior to classical NHCs.