5VP1

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 for the Treatment of Cognitive Disorders

Summary for 5VP1

• Entry DOI: 10.2210/pdb5vp1/pdb
• Related: 5VP0
• Descriptor: cGMP-dependent 3',5'-cyclic phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: inhibitor, phosphodiesterase, brain-pentrating, cognitive disorders, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Isoform PDE2A3: Cell membrane ; Lipid- anchor . Isoform PDE2A2: Mitochondrion matrix . Isoform PDE2A1: Cytoplasm . Isoform 5: Mitochondrion : O00408
• Total number of polymer chains: 3
• Total formula weight: 122457.95

Authors

Hoffman, I.D. (deposition date: 2017-05-03, release date: 2017-12-27, Last modification date: 2024-03-13)

Primary citation

Mikami, S.,Kawasaki, M.,Ikeda, S.,Negoro, N.,Nakamura, S.,Nomura, I.,Ashizawa, T.,Kokubo, H.,Hoffman, I.D.,Zou, H.,Oki, H.,Uchiyama, N.,Hiura, Y.,Miyamoto, M.,Itou, Y.,Nakashima, M.,Iwashita, H.,Taniguchi, T.
Discovery of a Novel Series of Pyrazolo[1,5-a]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from 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), for the Treatment of Cognitive Disorders.
Chem. Pharm. Bull., 65:1058-1077, 2017

PubMed 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.

PubMed: 29093293
DOI: 10.1248/cpb.c17-00564

Experimental method

X-RAY DIFFRACTION (1.86 Å)