1159795-35-3

Upstream product

• 23328-88-3 2-bromo-4-methyl-1H-imidazole 
• 66684-61-5 1,5-difluoro-3-methoxy-2-nitrobenzene 
• 151414-46-9 3,5-Difluoro-2-nitrophenol 
• 2713-34-0 3,5-difluorophenol 
• 67-56-1 methanol 
• 1159795-38-6 2-bromo-1-(3,5-difluoro-2-nitrophenyl)-4-methyl-1H-imidazole 
• 315-14-0 1,3,5-trifluoro-2-nitrobenzene 
• 93343-10-3 3,5-difluoroanisol 
• 1226805-66-8 1-(5-fluoro-3-methoxy-2-nitrophenyl)-4-methyl-1H-imidazole 

Downstream Products

• 1226805-67-9 3-(2-bromo-4-methyl-1H-imidazol-1-yl)-5-methoxy-4-nitrophenol 
• 1159795-37-5 N-(4-fluoro-2-methoxy-6-(4-methyl-2-(3-methylpyridin-4-yl)-1H-imidazol-1-yl)phenyl)acetamide 
• 1226804-27-8 8-fluoro-1-(3-fluoro-2-methylphenyl)-6-methoxy-3-methylimidazo[5,1-c][1,2,4]benzotriazine 
• 1226803-97-9 8-fluoro-6-methoxy-1-(3-methoxyphenyl)-3-methylimidazo[5,1-c][1,2,4]benzotriazine 
• 1226803-99-1 8-fluoro-6-methoxy-1-(2-methoxyphenyl)-3-methylimidazo[5,1-c][1,2,4]benzotriazine 

Relevant academic research and scientific papers

Novel triazines as potent and selective phosphodiesterase 10A inhibitors

The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t1/2, bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC50 = 1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED = 0.1 mg/kg) and conditioned avoidance responding (CAR; ID50 = 0.2 mg/kg).

Highly potent, selective, and orally active phosphodiesterase 10A inhibitors

The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC50 for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.

IMIDAZO[5,1-C][1,2,4]BENZOTRIAZINE DERIVATIVES AS INHIBITORS OF PHOSPHODIESTERASES

The invention relates to imidazo[5,1-c][1,2,4]benzotriazine derivatives of formula I: which are inhibitors of phosphodiesterase 2 or 10 useful in treating central nervous system diseases such as psychosis and also in treating, for example, obesity, type 2 diabetes, metabolic syndrome, glucose intolerance, and pain.

ARYL AND HETEROARYL FUSED IMIDAZO[1,5-a]PYRAZINES AS INHIBITORS OF PHOSPHODIESTERASE 10

The invention relates to imidazo[1,5-a]pyrazine derivatives, to processes for preparing them, to pharmaceutical preparations which comprise these compounds and to the pharmaceutical use of these compounds, which are inhibitors of phosphodiesterase 10 (PDE10), as active compounds for treating central nervous system diseases of mammals, including humans.