Design, synthesis, and evaluation of Leu*Ala hydroxyethylene-based non-peptide beta-secretase (BACE) inhibitors

Kun Xiao; Xin Li; Jingya Li; Lanping Ma; Bin Hu; Haiping Yu; Yan Fu; Rui Wang; Zeqiang Ma; Beiying Qiu; Jia Li; Dingyu Hu; Xin Wang; Jingkang Shen

doi:10.1016/j.bmc.2006.02.024

Design, synthesis, and evaluation of Leu*Ala hydroxyethylene-based non-peptide beta-secretase (BACE) inhibitors

Bioorg Med Chem. 2006 Jul 1;14(13):4535-51. doi: 10.1016/j.bmc.2006.02.024. Epub 2006 Feb 28.

Authors

Kun Xiao¹, Xin Li, Jingya Li, Lanping Ma, Bin Hu, Haiping Yu, Yan Fu, Rui Wang, Zeqiang Ma, Beiying Qiu, Jia Li, Dingyu Hu, Xin Wang, Jingkang Shen

Affiliation

¹ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Shanghai Institute for Biological Sciences, Graduate School of the Chinese Academy of Sciences, Chinese Academy of Sciences, PR China.

PMID: 16510290
DOI: 10.1016/j.bmc.2006.02.024

Abstract

With the aim of developing small molecular non-peptide beta-secretase (BACE) inhibitors, Leu*Ala hydroxyethylene (HE) was investigated as a scaffold to design and synthesize a series of compounds. Taking advantage of efficient combinatorial synthesis approaches and molecular modeling, extensive structure-activity relationship (SAR) studies were carried out on the N- and C-terminal residues of the Leu*Ala HE scaffold. Isobutyl amine was found to be an optimal C-cap, and suitable hydroxylalkylamines at the 3-position and nitro or methyl(methylsulfonyl)amine at the 5-position of isophthalamide as the N-terminus could form additional hydrogen bonds with BACE active sites and help improve potency. Many new potent non-peptide BACE inhibitors were identified in this study. Among them, compounds 37 and 44 exhibited excellent enzyme-inhibiting potency, comparable to that of OM99-2, and obvious inhibitory effects in cell-based assay with low molecular weights (<600).

Publication types

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

MeSH terms

Amyloid Precursor Protein Secretases
Aspartic Acid Endopeptidases
Benzamides / chemistry*
Carbamates / chemistry*
Dipeptides / chemistry*
Drug Design*
Endopeptidases / chemistry
Endopeptidases / drug effects*
Ethylenes / chemistry*
Humans
Molecular Structure
Nitrobenzenes / chemistry*
Oligopeptides / pharmacology
Peptides / pharmacology
Protease Inhibitors / chemical synthesis
Protease Inhibitors / chemistry*
Protease Inhibitors / pharmacology

Substances

Benzamides
Carbamates
Dipeptides
Ethylenes
Leu-Ala hydroxyethylene
N'-((4S,5S,7R)-7-(isobutylcarbamoyl)-5-hydroxy-2-methyloctan-4-yl)-N-((R)-1-hydroxy-3-methylbutan-2-yl)5-nitrobenzene-1,3-diamide
N'-((4S,5S,7R)-7-(isobutylcarbamoyl)-5-hydroxy-2-methyloctan-4-yl)-N-((S)-1-hydroxy-3-methylbutan-2-yl)5-(methyl(methylsulfonyl)amine)benzene-1,3-diamide
Nitrobenzenes
OM99-2
Oligopeptides
Peptides
Protease Inhibitors
Amyloid Precursor Protein Secretases
Endopeptidases
Aspartic Acid Endopeptidases
BACE1 protein, human