- PYRAZOLONE DERIVATIVE HAVING CYCLIC SIDE CHAIN
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PROBLEM TO BE SOLVED: To provide a compound that has excellent inhibitory action on ATPase activity of TIP48/TIP49 complex and is therefore useful for the treatment of tumor, or a pharmacologically acceptable salt thereof. SOLUTION: The present invention provides a compound having a structure represented by general formula (I), its pharmacologically acceptable salt, or a pharmaceutical composition comprising the compound (where R1, R2, R3, R4, R5, R6, R7, W, and Z are as defined in the specifications). SELECTED DRAWING: None COPYRIGHT: (C)2016,JPOandINPIT
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Paragraph 0254; 0255
(2016/10/08)
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- Optimization of brain penetrant 11β-hydroxysteroid dehydrogenase type i inhibitors and in vivo testing in diet-induced obese mice
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11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) has been widely considered by the pharmaceutical industry as a target to treat metabolic syndrome in type II diabetics. We hypothesized that central nervous system (CNS) penetration might be required to see efficacy. Starting from a previously reported pyrimidine compound, we removed hydrogen-bond donors to yield 3, which had modest CNS penetration. More significant progress was achieved by changing the core to give 40, which combines good potency and CNS penetration. Compound 40 was dosed to diet-induced obese (DIO) mice and gave excellent target engagement in the liver and high free exposures of drug, both peripherally and in the CNS. However, no body weight reduction or effects on glucose or insulin were observed in this model. Similar data were obtained with a structurally diverse thiazole compound 51. This work casts doubt on the hypothesis that localized tissue modulation of 11β-HSD1 activity alleviates metabolic syndrome.
- Goldberg, Frederick W.,Dossetter, Alexander G.,Scott, James S.,Robb, Graeme R.,Boyd, Scott,Groombridge, Sam D.,Kemmitt, Paul D.,Sj?gren, Tove,Gutierrez, Pablo Morentin,Deschoolmeester, Joanne,Swales, John G.,Turnbull, Andrew V.,Wild, Martin J.
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supporting information
p. 970 - 986
(2014/03/21)
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- 2 -AMINOPYRIMIDINE DERIVATIVES AS HISTAMINE H4 ANTAGONISTS
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2-Amino-pyrimidine derivatives of formula I, wherein the meaning of the different substituents are those indicated in the description. These compounds are useful as histamine receptor H4antagonists.
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Page/Page column 107
(2009/07/18)
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