- 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
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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.
- 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
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supporting information
p. 7677 - 7702
(2017/10/06)
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- NITROGENATED HETEROCYCLIC COMPOUND
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The present invention provides a compound having a PDE2A selective inhibitory action, which is useful as an agent for the prophylaxis or treatment of schizophrenia, Alzheimer's disease and the like. The present invention is a compound represented by the formula (1): wherein each symbol is as described in the specification, or a salt thereof.
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Paragraph 0881
(2015/03/28)
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- CYCLOBUTENEDIONE DERIVATIVES
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The present invention relates to compounds of the formula (I): to pharmaceutically acceptable salts therefore and to pharmaceutically acceptable solvates of said compounds and salts, wherein the substituents are defined herein; to compositions containing such compounds; and to the uses of such compounds in the treatment of various diseases, particularly inflammatory conditions.
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Page/Page column 73-74
(2010/12/17)
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- Chemical and biological investigation of cyclopropyl containing diaryl-pyrazole-3-carboxamides as novel and potent cannabinoid type 1 receptor antagonists
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Obesity is a major clinical problem in the western world, and many molecular targets have been explored in the search for effective therapeutic agents. One of these, antagonism of the cannabinoid 1 (CB1) receptor, rose to prominence following reports demo
- Szabó, Gyorgy,Varga, Balázs,Páyer-Lengyel, Dóra,Szemzo, Attila,Erdélyi, Péter,Vukics, Krisztina,Szikra, Judit,Hegyi, éva,Vastag, Mónika,Kiss, Béla,Laszy, Judit,Gyertyán, István,Fischer, János
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supporting information; experimental part
p. 4329 - 4337
(2010/02/28)
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- NOVEL CB1 ANTAGONISTS AND THEIR PREPARATION
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The invention relates to new compounds of general formula (I) acting as CB1 antagonists and to their preparation. The compounds according to this invention can be used for the treatment of obesity, behavioral addictions, psychiatric and metabolic disorder
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Page/Page column 13
(2008/12/06)
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- ALPHA-UNSUBSTITUTED ARYLMETHYL PIPERAZINE PYRAZOLO[1,5-A] PYRIMIDINE AMIDE DERIVATIVES
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Methods of preventing, treating or delaying the onset of HIV in a subject by administering to the subject novel pharmaceutically active arylmethyl pyrazolo[1,5-α ]pyrimidine amide derivatives, or pharmaceutical compositions containing the same are described. Additionally, compounds of novel pharmaceutically active arylmethyl piperazine pyrazolo[l,5-α]pyrimidine amide derivatives and their use for the manufacture of specific medicaments are described.
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Page/Page column 130-131
(2008/12/08)
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