Highlighted Paper selected by Editor-in-Chief : 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

  • Mikami Satoshi
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Kawasaki Masanori
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Ikeda Shuhei
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Negoro Nobuyuki
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Nakamura Shinji
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Nomura Izumi
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Ashizawa Tomoko
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Kokubo Hironori
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Hoffman Isaac Dylan
    Takeda California, Inc.
  • Zou Hua
    Takeda California, Inc.
  • Oki Hideyuki
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Uchiyama Noriko
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Hiura Yuuto
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Miyamoto Maki
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Itou Yuuki
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Nakashima Masato
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Iwashita Hiroki
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited
  • Taniguchi Takahiko
    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited

書誌事項

タイトル別名
  • Discovery of a Novel Series of Pyrazolo[1,5-<i>a</i>]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from <i>N</i>-((1<i>S</i>)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-<i>b</i>]pyrazine-4(1<i>H</i>)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders

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説明

<p>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.</p>

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