Novel BACE1 inhibitors with a non-acidic heterocycle at the P1' position

Kenji Suzuki; Yoshio Hamada; Jeffrey-Tri Nguyen; Yoshiaki Kiso

doi:10.1016/j.bmc.2013.08.016

Novel BACE1 inhibitors with a non-acidic heterocycle at the P1' position

Bioorg Med Chem. 2013 Nov 1;21(21):6665-73. doi: 10.1016/j.bmc.2013.08.016. Epub 2013 Aug 12.

Authors

Kenji Suzuki¹, Yoshio Hamada, Jeffrey-Tri Nguyen, Yoshiaki Kiso

Affiliation

¹ Department of Medicinal Chemistry, Center for Frontier Research in Medicinal Science and 21st Century COE Program, Kyoto Pharmaceutical University, Yamashina-ku, Kyoto 607-8412, Japan.

PMID: 23993670
DOI: 10.1016/j.bmc.2013.08.016

Abstract

We have reported potent peptidic and non-peptidic BACE1 inhibitors with a hydroxymethylcarbonyl (HMC) isostere as a substrate transition-state mimic. However, our potent inhibitors possess a tetrazole ring at the P1' position. It is desirable that central nervous system (CNS) drugs do not possess an acidic moiety. In this study, we synthesized non-acidic BACE1 inhibitors with heterocyclic derivatives at the P1' position. KMI-1764 (27) exhibited potent inhibitory activity (IC50=27nM). Interestingly, these non-acidic inhibitors tended to follow the quantitative structure-activity relationship (QSAR) equation and interacted with BACE1-Arg235 in the binding model.

Keywords: Alzheimer’s disease; Hydroxymethylcarbonyl isostere; Non-acidic inhibitor; Quantitative structure–activity relationship; β-Secretase.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amyloid Precursor Protein Secretases / antagonists & inhibitors*
Amyloid Precursor Protein Secretases / genetics
Amyloid Precursor Protein Secretases / metabolism
Aspartic Acid Endopeptidases / antagonists & inhibitors*
Aspartic Acid Endopeptidases / genetics
Aspartic Acid Endopeptidases / metabolism
Benzamides / chemical synthesis
Benzamides / chemistry*
Benzamides / metabolism
Heterocyclic Compounds / chemical synthesis
Heterocyclic Compounds / chemistry*
Heterocyclic Compounds / metabolism
Humans
Hydrogen Bonding
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / metabolism
Protein Binding
Quantitative Structure-Activity Relationship
Recombinant Proteins / biosynthesis
Recombinant Proteins / chemistry
Recombinant Proteins / genetics
Thiadiazoles / chemical synthesis
Thiadiazoles / chemistry*
Thiadiazoles / metabolism

Substances

Benzamides
Heterocyclic Compounds
N1-(4-(5-bromo-1,3,4-thiadiazol-2-ylamino)-3-hydroxy-4-oxo-1-phenylbutan-2-yl)-5-(N-methylmethanesulfonamido)-N3-(1-phenylethyl)isophthalamide
Protease Inhibitors
Recombinant Proteins
Thiadiazoles
Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
BACE1 protein, human