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

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

Affiliation

  • 1 Discovery Chemistry, Pharma Research & Early Development, Grenzacherstrasse 124, Basel CH-4070, Switzerland. hans.hilpert@roche.com
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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