title: Aminothiazoles as γ-secretase modulators.
abstract: We herein report the discovery of a new γ-secretase modulator class with an aminothiazole core starting from a HTS hit (3). Synthesis and SAR of this series are discussed. These novel compounds demonstrate moderate to good in vitro potency in inhibiting amyloid beta (Aβ) peptide production. Overall γ-secretase is not inhibited but the formation of the aggregating, toxic Aβ42 peptide is shifted to smaller non-aggregating Aβ peptides. Compound 15 reduced brain Aβ42 in vivo in APPSwe transgenic mice at 30mg/kg p.o.
authors.affiliation: Discovery Chemistry, F. Hoffmann-La Roche Ltd, Grenzacher Strasse 124, 4070 Basel, Switzerland. thomas.luebbers@roche.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Lübbers
authors.forename: Alexander
authors.initials: A
authors.lastname: Flohr
authors.forename: Synese
authors.initials: S
authors.lastname: Jolidon
authors.forename: Pascale
authors.initials: P
authors.lastname: David-Pierson
authors.forename: Helmut
authors.initials: H
authors.lastname: Jacobsen
authors.forename: Laurence
authors.initials: L
authors.lastname: Ozmen
authors.forename: Karlheinz
authors.initials: K
authors.lastname: Baumann
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000187:drug effects*; D000818:Animals; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D013844:Thiazoles; D053829:Amyloid Precursor Protein Secretases