Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: discovery of PF-3084014.
| Autor: | Brodney MA; Neuroscience Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Eastern Point Road, Groton, CT 06340, USA. michael.a.brodney@pfizer.com, Auperin DD, Becker SL, Bronk BS, Brown TM, Coffman KJ, Finley JE, Hicks CD, Karmilowicz MJ, Lanz TA, Liston D, Liu X, Martin BA, Nelson RB, Nolan CE, Oborski CE, Parker CP, Richter KE, Pozdnyakov N, Sahagan BG, Schachter JB, Sokolowski SA, Tate B, Wood DE, Wood KM, Van Deusen JW, Zhang L |
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| Jazyk: | angličtina |
| Zdroj: | Bioorganic & medicinal chemistry letters [Bioorg Med Chem Lett] 2011 May 01; Vol. 21 (9), pp. 2637-40. Date of Electronic Publication: 2010 Dec 30. |
| DOI: | 10.1016/j.bmcl.2010.12.118 |
| Abstrakt: | 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 EC(50) lead to the identification of compound 14f (PF-3084014) which was selected for clinical development. (Copyright © 2011 Elsevier Ltd. All rights reserved.) |
| Databáze: | MEDLINE |
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