ABSTRACT
It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3',5'-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.
Subject(s)
Cognition Disorders/drug therapy , Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors , Drug Discovery , Phosphodiesterase Inhibitors/pharmacology , Pyrazines/pharmacology , Pyrazoles/pharmacology , Pyridines/pharmacology , Pyrimidines/pharmacology , 3T3 Cells , Administration, Oral , Animals , COS Cells , Cell Survival/drug effects , Chlorocebus aethiops , Cognition Disorders/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Dose-Response Relationship, Drug , Humans , Male , Mice , Mice, Inbred BALB C , Mice, Inbred ICR , Molecular Structure , Phosphodiesterase Inhibitors/administration & dosage , Phosphodiesterase Inhibitors/chemistry , Powder Diffraction , Pyrazines/chemistry , Pyrazoles/chemistry , Pyridines/chemistry , Pyrimidines/chemistry , Rats , Rats, Long-Evans , Solubility , Structure-Activity Relationship , ThermodynamicsABSTRACT
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.
Subject(s)
Brain/drug effects , Cognition/drug effects , Cyclic Nucleotide Phosphodiesterases, Type 2/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacology , Phosphodiesterase Inhibitors/pharmacokinetics , Pyrazines/pharmacology , Pyrazines/pharmacokinetics , Animals , Brain/metabolism , Cognition Disorders/drug therapy , Cognition Disorders/metabolism , Crystallography, X-Ray , Cyclic GMP/metabolism , Cyclic Nucleotide Phosphodiesterases, Type 2/chemistry , Cyclic Nucleotide Phosphodiesterases, Type 2/metabolism , Drug Design , Halogenation , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred ICR , Phosphodiesterase Inhibitors/chemistry , Pyrazines/chemistry , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Pyrimidines/chemistry , Pyrimidines/pharmacokinetics , Pyrimidines/pharmacology , Rats , Rats, Sprague-DawleyABSTRACT
The atropo-enantioselective borohydride reduction with dynamic kinetic resolution of biaryl lactones was catalyzed by an optically active beta-ketoiminatocobalt(II) complex to afford optically active biaryl compounds. Chiral HPLC analysis of the starting biaryl lactones was performed at various temperatures to determine suitable reaction conditions for dynamic kinetic resolution. Various types of axially chiral biaryl compounds were obtained with high enantioselectivity.