β-Secretase (BACE1) inhibitors with high in vivo efficacy suitable for clinical evaluation in Alzheimer's disease

  • J Med Chem. 2013 May 23;56(10):3980-95. doi: 10.1021/jm400225m.
Hans Hilpert  1 ,  Wolfgang Guba ,  Thomas J Woltering ,  Wolfgang Wostl ,  Emmanuel Pinard ,  Harald Mauser ,  Alexander V Mayweg ,  Mark Rogers-Evans ,  Roland Humm ,  Daniela Krummenacher ,  Thorsten Muser ,  Christian Schnider ,  Helmut Jacobsen ,  Laurence Ozmen ,  Alessandra Bergadano ,  David W Banner ,  Remo Hochstrasser ,  Andreas Kuglstatter ,  Pascale David-Pierson ,  Holger Fischer ,  Alessandra Polara ,  Robert Narquizian
Affiliations
  • 1. Discovery Chemistry, Pharma Research & Early Development, Grenzacherstrasse 124, Basel CH-4070, Switzerland. [email protected]
PMID: 23590342 DOI: 10.1021/jm400225m
Abstract

An extensive fluorine scan of 1,3-oxazines revealed the power of fluorine(s) to lower the PKA and thereby dramatically change the pharmacological profile of this class of BACE1 inhibitors. The CF3 substituted oxazine 89, a potent and highly brain penetrant BACE1 Inhibitor, was able to reduce significantly CSF Aβ40 and 42 in rats at oral doses as low as 1 mg/kg. The effect was long lasting, showing a significant reduction of Aβ40 and 42 even after 24 h. In contrast to 89, compound 1b lacking the CF3 group was virtually inactive in vivo.

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