- Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: Discovery of PF-3084014
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A novel series of tetralin containing amino imidazoles, derived from modification of the corresponding phenyl acetic acid derivatives is described. Replacement of the amide led to identification of a potent series of tetralin-amino imidazoles with robust central efficacy. The reduction of brain Aβ in guinea pigs in the absence of changes in B-cells suggested a potential therapeutic index with respect to APP processing compared with biomarkers of notch related toxicity. Optimization of the FTOC to plasma concentrations at the brain Aβ EC50 lead to the identification of compound 14f (PF-3084014) which was selected for clinical development.
- Brodney, Michael A.,Auperin, David D.,Becker, Stacey L.,Bronk, Brian S.,Brown, Tracy M.,Coffman, Karen J.,Finley, James E.,Hicks, Carol D.,Karmilowicz, Michael J.,Lanz, Thomas A.,Liston, Dane,Liu, Xingrong,Martin, Barbara-Anne,Nelson, Robert B.,Nolan, Charles E.,Oborski, Christine E.,Parker, Christine P.,Richter, Karl E.G.,Pozdnyakov, Nikolay,Sahagan, Barbara G.,Schachter, Joel B.,Sokolowski, Sharon A.,Tate, Barbara,Wood, Douglas E.,Wood, Kathleen M.,Van Deusen, Jeffrey W.,Zhang, Lei
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p. 2637 - 2640
(2011/06/20)
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- Imidazole compounds for the treatment of neurological disorders
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The present invention relates to compounds of Formula I wherein R1, R2, R3, R4, R6, R7 and A are as defined. Compounds of Formula I have activity inhibiting production of Aβ-peptide. The invention also relates to pharmaceutical compositions and methods for treating diseases and disorders, for example, neurodegenerative and/or neurological disorders, e.g., Alzheimer's disease, in a mammal comprising compounds of Formula I.
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Page/Page column 29
(2010/11/26)
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- IMIDAZOLE COMPOUNDS FOR THE TREATMENT OF NEURODEGENERATIVE DISORDERS
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The present invention relates to compounds of the Formula (I) wherein R1, R2, R3, R4, R5, R6, R7 and A are as defined. Compounds of the Formula (I) have activity inhibiting produ
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Page/Page column 78-79
(2010/02/14)
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