bay-60-7550 has been researched along with Cognition-Disorders* in 3 studies
1 review(s) available for bay-60-7550 and Cognition-Disorders
Article | Year |
---|---|
PDE2 inhibition: potential for the treatment of cognitive disorders.
Phosphodiesterase inhibition has received much attention in the past 20 years for the potential treatment of CNS disorders. A primary focus of this work is the enhancement of memory and/or cognitive functioning. The role of PDEs in the augmentation of cyclic nucleotide signaling makes these enzymes attractive targets for enhancing the effects of neuronal communication. This review focuses on recent findings with respect to the role of PDE2 inhibition in cognitive functioning. Special attention is paid to recently disclosed, selective tool compounds and the use of these tool compounds to support the role of PDE2 inhibition in cognition. Recently reported SAR and modeling work will be presented along with discussion of the entry of new PDE2 inhibitors into the clinic. Topics: Animals; Cognition Disorders; Cyclic Nucleotide Phosphodiesterases, Type 2; Humans; Ligands; Permeability; Phosphodiesterase Inhibitors; Protein Binding; Quinolones; Structure-Activity Relationship | 2013 |
2 other study(ies) available for bay-60-7550 and Cognition-Disorders
Article | Year |
---|---|
Discovery of an Orally Bioavailable, Brain-Penetrating, in Vivo Active Phosphodiesterase 2A Inhibitor Lead Series for the Treatment of Cognitive Disorders.
Herein, we describe the discovery of a potent, selective, brain-penetrating, in vivo active phosphodiesterase (PDE) 2A inhibitor lead series. To identify high-quality leads suitable for optimization and enable validation of the physiological function of PDE2A in vivo, structural modifications of the high-throughput screening hit 18 were performed. Our lead generation efforts revealed three key potency-enhancing functionalities with minimal increases in molecular weight (MW) and no change in topological polar surface area (TPSA). Combining these structural elements led to the identification of 6-methyl-N-((1R)-1-(4-(trifluoromethoxy)phenyl)propyl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (38a), a molecule with the desired balance of preclinical properties. Further characterization by cocrystal structure analysis of 38a bound to PDE2A uncovered a unique binding mode and provided insights into its observed potency and PDE selectivity. Compound 38a significantly elevated 3',5'-cyclic guanosine monophosphate (cGMP) levels in mouse brain following oral administration, thus validating this compound as a useful pharmacological tool and an attractive lead for future optimization. Topics: Administration, Oral; Animals; Brain; Cognition Disorders; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Drug Discovery; Humans; Male; Mice; Mice, Inbred ICR; Molecular Docking Simulation; Phosphodiesterase Inhibitors; Pyrimidines; Rats | 2017 |
Discovery of Clinical Candidate N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915): A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor
Phosphodiesterase (PDE) 2A inhibitors have emerged as a novel mechanism with potential therapeutic option to ameliorate cognitive dysfunction in schizophrenia or Alzheimer's disease through upregulation of cyclic nucleotides in the brain and thereby achieve potentiation of cyclic nucleotide signaling pathways. This article details the expedited optimization of our recently disclosed pyrazolo[1,5-a]pyrimidine lead compound 4b, leading to the discovery of clinical candidate 36 (TAK-915), which demonstrates an appropriate combination of potency, PDE selectivity, and favorable pharmacokinetic (PK) properties, including brain penetration. Successful identification of 36 was realized through application of structure-based drug design (SBDD) to further improve potency and PDE selectivity, coupled with prospective design focused on physicochemical properties to deliver brain penetration. Oral administration of 36 demonstrated significant elevation of 3',5'-cyclic guanosine monophosphate (cGMP) levels in mouse brains and improved cognitive performance in a novel object recognition task in rats. Consequently, compound 36 was advanced into human clinical trials. Topics: Animals; Brain; Cognition; Cognition Disorders; Crystallography, X-Ray; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 2; Drug Design; Halogenation; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Phosphodiesterase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Rats; Rats, Sprague-Dawley | 2017 |