2. Academic Validation
  3. Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: discovery of PF-3084014

Design, synthesis, and in vivo characterization of a novel series of tetralin amino imidazoles as γ-secretase inhibitors: discovery of PF-3084014

  • Bioorg Med Chem Lett. 2011 May 1;21(9):2637-40. doi: 10.1016/j.bmcl.2010.12.118.
Michael A Brodney 1,  David D Auperin,  Stacey L Becker,  Brian S Bronk,  Tracy M Brown,  Karen J Coffman,  James E Finley,  Carol D Hicks,  Michael J Karmilowicz,  Thomas A Lanz,  Dane Liston,  Xingrong Liu,  Barbara-Anne Martin,  Robert B Nelson,  Charles E Nolan,  Christine E Oborski,  Christine P Parker,  Karl E G Richter,  Nikolay Pozdnyakov,  Barbara G Sahagan,  Joel B Schachter,  Sharon A Sokolowski,  Barbara Tate,  Douglas E Wood,  Kathleen M Wood,  Jeffrey W Van Deusen,  Lei Zhang
Affiliations

Affiliation

  • 1 Neuroscience Medicinal Chemistry, Pfizer PharmaTherapeutics Research and Development, Eastern Point Road, Groton, CT 06340, USA. michael.a.brodney@pfizer.com
PMID: 21269827 DOI: 10.1016/j.bmcl.2010.12.118
Abstract

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.

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