- PYRIMIDOPYRIMIDINONES USEFUL AS WEE-1 KINASE INHIBITORS
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The present invention relates to compounds that are useful as inhibitors of the activity of Wee-1 kinase. The present invention also relates to pharmaceutical compositions comprising these compounds and to methods of using these compounds in the treatment of cancer and methods of treating cancer.
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- Structure-activity relationship of quinoline derivatives as potent and selective α2c-adrenoceptor antagonists
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Starting from two acridine compounds identified in a high-throughput screening campaign (1 and 2, Table 1), a series of 4-aminoquinolines was synthesized and tested for their properties on the human α2- adrenoceptor subtypes (α2A, α2B, and α2C). A number of compounds with good antagonist potencies against the α2C-adrenoceptor and excellent subtype selectivities over the other two subtypes were discovered. For example, (R)-{4-[4-(3,4-dimethylpiperazin-1-yl)phenylamino]quinolin-3-yl}methanol 6j had an antagonist potency of 8.5 nM against, and a subtype selectivity of more than 200-fold for, the α2c-adrenoceptor. Investigation of the structure-activity relationship identified a number of structural features, the most critical of which was an absolute need for a substituent in the 3-position of the quinoline ring. The 3-position on the piperazine ring was also found to play an appreciable role, as substitutions in that position exerted a significant and stereospecific beneficial effect on the α2C- adrenoceptor affinity and potency. Replacing the piperazine ring proved difficult, with 1,4-diazepanes representing the only viable alternative.
- H?glund, Iisa P. J.,Silver, Satu,Engstr?m, Mia T.,Salo, Harri,Tauber, Andrei,Kyyr?nen, Hanna-Kaisa,Saarenketo, Pauli,Hoffrén, Anna-Marja,Kokko, Kurt,Pohjanoksa, Katariina,Sallinen, Jukka,Savola, Juha-Matti,Wurster, Siegfried,Kallatsa, Oili A.
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p. 6351 - 6363
(2007/10/03)
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