295327-27-4Relevant academic research and scientific papers
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
Mikami, Satoshi,Nakamura, Shinji,Ashizawa, Tomoko,Nomura, Izumi,Kawasaki, Masanori,Sasaki, Shigekazu,Oki, Hideyuki,Kokubo, Hironori,Hoffman, Isaac D.,Zou, Hua,Uchiyama, Noriko,Nakashima, Kosuke,Kamiguchi, Naomi,Imada, Haruka,Suzuki, Noriko,Iwashita, Hiroki,Taniguchi, Takahiko
, p. 7677 - 7702 (2017/10/06)
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.
HETEROCYCLIC COMPOUND
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, (2016/06/28)
A compound represented by the formula (I): wherein each symbol is as described in the SPECIFICATION, or a salt thereof has a PDE2A inhibitory action, and is useful as a prophylactic or therapeutic drug for schizophrenia, Alzheimer's disease and the like.
Preparation of azaindolines and benzoyl substituted azaindolines: Precursors of triazabenzo[cd]azulen-9-one PDE4 inhibitors
Badland, Matthew,Devillers, Ingrid,Durand, Corinne,Fasquelle, Véronique,Gaudillire, Bernard,Jacobelli, Henry,Manage, Ajith C.,Pevet, Isabelle,Puaud, Jocelyne,Shorter, Anthony J.,Wrigglesworth, Roger
, p. 5292 - 5296 (2011/10/30)
The syntheses of various substituted azaindolines are described. Azaindolines were identified as potential key intermediates towards new PDE4 inhibitors.
Discovery and in vitro evaluation of potent TrkA kinase inhibitors: Oxindole and aza-oxindoles
Wood, Edgar R.,Kuyper, Lee,Petrov, Kimberly G.,Hunter III, Robert N.,Harris, Philip A.,Lackey, Karen
, p. 953 - 957 (2007/10/03)
The discovery, synthesis, potential binding mode, and in vitro kinase profile of 3-(3-bromo-4-hydroxy-5-(2′-methoxyphenyl)-benzylidene)-5-bromo- 1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one, 3-[(1-methyl-1H-indol-3-yl)methylene]- 1,3-dihydro-2H-pyrrolo[3,2-b]-pyridin-2-one as potent TrkA inhibitors are discussed.
Substituted aza-oxindole derivatives
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, (2008/06/13)
Substituted aza-oxindole derivatives useful as cyclin dependent kinase 11 inhibitors, for preventing/reducing the severity of epithelial cytotoxicity side-effects (e.g., alopecia, plantar-palmar syndrome, mucositis) induced by chemoptherapy and/or radiati
Thrombin inhibitors
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Page 24, (2008/06/13)
Compounds of the invention are useful in inhibiting thrombin and associated thrombotic occlusions having the following structure: or a pharmaceutically acceptable salt thereof.
3-(anilinomethylene) oxindoles
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Page column 72, (2010/02/04)
The present invention relates generally to novel amine substituted oxindole compounds and compositions. Such compounds and compositions have utility as pharmacological agents in treating diseases or conditions alleviated by the inhibition or antagonism of
