- Discovery of a Novel, Highly Potent, and Selective Thieno[3,2- d]pyrimidinone-Based Cdc7 Inhibitor with a Quinuclidine Moiety (TAK-931) as an Orally Active Investigational Antitumor Agent
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In our pursuit of developing a novel, potent, and selective cell division cycle 7 (Cdc7) inhibitor, we optimized the previously reported thieno[3,2-d]pyrimidinone analogue I showing time-dependent Cdc7 kinase inhibition and slow dissociation kinetics. These medicinal chemistry efforts led to the identification of compound 3d, which exhibited potent cellular activity, excellent kinase selectivity, and antitumor efficacy in a COLO205 xenograft mouse model. However, the issue of formaldehyde adduct formation emerged during a detailed study of 3d, which was deemed an obstacle to further development. A structure-based approach to circumvent the adduct formation culminated in the discovery of compound 11b (TAK-931) possessing a quinuclidine moiety as a preclinical candidate. In this paper, the design, synthesis, and biological evaluation of this series of compounds will be presented.
- Kurasawa, Osamu,Miyazaki, Tohru,Homma, Misaki,Oguro, Yuya,Imada, Takashi,Uchiyama, Noriko,Iwai, Kenichi,Yamamoto, Yukiko,Ohori, Momoko,Hara, Hideto,Sugimoto, Hiroshi,Iwata, Kentaro,Skene, Robert,Hoffman, Isaac,Ohashi, Akihiro,Nomura, Toshiyuki,Cho, Nobuo
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p. 1084 - 1104
(2020/02/05)
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- Nickel-Catalyzed Asymmetric Reductive Cross-Coupling between Heteroaryl Iodides and α-Chloronitriles
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A Ni-catalyzed asymmetric reductive cross-coupling of heteroaryl iodides and α-chloronitriles has been developed. This method furnishes enantioenriched α,α-disubstituted nitriles from simple organohalide building blocks. The reaction tolerates a variety of heterocyclic coupling partners, including pyridines, pyrimidines, quinolines, thiophenes, and piperidines. The reaction proceeds under mild conditions at room temperature and precludes the need to pregenerate organometallic nucleophiles.
- Kadunce, Nathaniel T.,Reisman, Sarah E.
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supporting information
p. 10480 - 10483
(2015/09/28)
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- A practical synthesis of S-quinuclidine-2-carboxylic acid and its enantiomer
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A short and convenient synthesis of (S)- and (R)-quinuclidine-2-carboxylic acids has been developed. The resolution of enantiomers has been accomplished by both chemical and enzymic means.
- Mi, Yuan,Corey
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p. 2515 - 2516
(2007/10/03)
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