ABSTRACT
The discovery, design and synthesis of a new series of GSMs is described. The classical imidazole heterocycle has been replaced by a cyano group attached to an indole nucleus. The exploration of this series has led to compound 26-S which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Subject(s)
Amyloid Precursor Protein Secretases/metabolism , Indoles/chemical synthesis , Drug Design , Humans , Structure-Activity RelationshipABSTRACT
The design and synthesis of a novel series of potent gamma secretase modulators is described. Exploration of various spacer groups between the triazole ring and the aromatic appendix in 2 has led to anilinotriazole 28, which combined high in vitro and in vivo potency with an acceptable drug-like profile.
Subject(s)
Amyloid Precursor Protein Secretases/antagonists & inhibitors , Aniline Compounds/chemistry , Triazoles/chemistry , Amyloid Precursor Protein Secretases/metabolism , Amyloid beta-Peptides/chemistry , Amyloid beta-Peptides/metabolism , Aniline Compounds/chemical synthesis , Aniline Compounds/metabolism , Animals , Brain/metabolism , Drug Design , Humans , Mice , Mice, Transgenic , Protein Binding , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/metabolismABSTRACT
The evolution of amide 3 into conformationally restricted bicyclic triazolo-piperidine 14-S as a γ-secretase modulator is described. This is a potential disease modifying anti-Alzheimer's drug which demonstrated high in vitro and in vivo potency against Aß42 peptide, reduced lipophilicity and enhanced brain free fraction compared to the previous series.
