Rational design and synthesis of aminopiperazinones as β-secretase (BACE) inhibitors

Gary Tresadern; Francisca Delgado; Oscar Delgado; Harrie Gijsen; Gregor J Macdonald; Dieder Moechars; Frederik Rombouts; Richard Alexander; John Spurlino; Michiel Van Gool; Juan Antonio Vega; Andrés A Trabanco

doi:10.1016/j.bmcl.2011.10.050

Rational design and synthesis of aminopiperazinones as β-secretase (BACE) inhibitors

Bioorg Med Chem Lett. 2011 Dec 15;21(24):7255-60. doi: 10.1016/j.bmcl.2011.10.050. Epub 2011 Oct 20.

Authors

Gary Tresadern¹, Francisca Delgado, Oscar Delgado, Harrie Gijsen, Gregor J Macdonald, Dieder Moechars, Frederik Rombouts, Richard Alexander, John Spurlino, Michiel Van Gool, Juan Antonio Vega, Andrés A Trabanco

Affiliation

¹ Research Informatics & Integrative Genomics, Calle Jarama 75, Poligono Industrial, Toledo 45007, Spain. [email protected]

PMID: 22071305
DOI: 10.1016/j.bmcl.2011.10.050

Abstract

Aminopiperazinone inhibitors of BACE were identified by rational design. Structure based design guided idea prioritization and initial racemic hit 18a showed good activity. Modification in decoration and chiral separation resulted in the 40 nM inhibitor, (-)-37, which showed in vivo reduction of amyloid beta peptides. The crystal structure of 18a showed a binding mode driven by interaction with the catalytic aspartate dyad and distribution of the biaryl amide decoration towards S1 and S3 pockets.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Binding Sites
Computer Simulation
Drug Design*
Enzyme Activation / drug effects
Enzyme Inhibitors / chemical synthesis*
Enzyme Inhibitors / chemistry
Enzyme Inhibitors / pharmacology
Piperazines / chemical synthesis
Piperazines / chemistry*
Piperazines / pharmacology
Protein Structure, Tertiary
Stereoisomerism

Substances

Enzyme Inhibitors
Piperazines
Amyloid Precursor Protein Secretases