Design and optimization of tricyclic gamma-secretase modulators

Jianliang Shi; Dmitry Zuev; Li Xu; Kimberley A Lentz; James E Grace; Jeremy H Toyn; Richard E Olson; John E Macor; Lorin A Thompson

doi:10.1016/j.bmcl.2015.06.020

Design and optimization of tricyclic gamma-secretase modulators

Bioorg Med Chem Lett. 2016 Mar 1;26(5):1498-502. doi: 10.1016/j.bmcl.2015.06.020. Epub 2015 Jun 12.

Authors

Jianliang Shi¹, Dmitry Zuev², Li Xu², Kimberley A Lentz², James E Grace², Jeremy H Toyn², Richard E Olson², John E Macor², Lorin A Thompson²

Affiliations

¹ Discovery, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA. Electronic address: [email protected].
² Discovery, Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, CT 06492, USA.

PMID: 26848108
DOI: 10.1016/j.bmcl.2015.06.020

Abstract

Beginning with a diaminotriazine screening hit, several series of novel, tricyclic gamma-secretase modulators (GSMs) were designed. The SAR of several related series of GSMs is presented, and the in vivo profile of a lead molecule from the series is described.

Keywords: Alzheimer’s disease; CYP3A4 inhibition; Gamma-secretase modulators.

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / metabolism
Aniline Compounds / chemical synthesis
Aniline Compounds / chemistry
Aniline Compounds / pharmacology*
Animals
Dose-Response Relationship, Drug
Drug Design*
Humans
Mice
Molecular Structure
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology*
Structure-Activity Relationship
Triazines / chemical synthesis
Triazines / chemistry
Triazines / pharmacology*

Substances

Aniline Compounds
Protease Inhibitors
Triazines
Amyloid Precursor Protein Secretases
aniline