- VIRAL REPLICATION INHIBITORS
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The present invention relates to a series of novel compounds, methods to prevent or treat viral infections in animals by using the novel compounds and to said novel compounds for use as a medicine, more preferably for use as a medicine to treat or prevent viral infections, particularly infections with RNA viruses, more particularly infections with viruses belonging to the family of the Flaviviridae, and yet more particularly infections with the Dengue virus. The present invention furthermore relates to pharmaceutical compositions or combination preparations of the novel compounds, to the compositions or preparations for use as a medicine, more preferably for the prevention or treatment of viral infections. The invention also relates to processes for preparation of the compounds.
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Page/Page column 200
(2013/04/13)
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- Rational evolution of a novel type of potent and selective proviral integration site in moloney murine leukemia virus kinase 1 (PIM1) inhibitor from a screening-hit compound
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Serine/threonine kinase PIM1 is an emerging therapeutic target for hematopoietic and prostate cancer therapy. To develop a novel PIM1 inhibitor, we focused on 1, a metabolically labile, nonselective kinase inhibitor discovered in our previous screening study. We adopted a rational optimization strategy based mainly on structural information for the PIM1-1 complex to improve the potency and selectivity. This approach afforded the potent and metabolically stable PIM1-selective inhibitor 14, which shows only a marginal increase in molecular weight compared with 1 but has a significantly decreased cLogP. The validity of our design concept was confirmed by X-ray structure analysis. In a cellular study, 14 potently inhibited the growth of human leukemia cell line MV4-11 but had a negligible effect on the growth of WI-38 (surrogate for general toxicity). These results demonstrate the effectiveness of our design strategy for evolving the screening-hit compound 1 into a novel type of PIM1 inhibitor, 14.
- Nakano, Hirofumi,Saito, Nae,Parker, Lorien,Tada, Yukio,Abe, Masanao,Tsuganezawa, Keiko,Yokoyama, Shigeyuki,Tanaka, Akiko,Kojima, Hirotatsu,Okabe, Takayoshi,Nagano, Tetsuo
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experimental part
p. 5151 - 5164
(2012/08/29)
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