Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position

• Published in: Bioorganic & medicinal chemistry letters 2012-07, Vol.22 (14), p.4640-4644
• Main Authors: Hamada, Yoshio, Nakanishi, Tomoya, Suzuki, Kenji, Yamaguchi, Ryoji, Hamada, Takashi, Hidaka, Koushi, Ishiura, Shoichi, Kiso, Yoshiaki
• Format: Article
• Language: English
• Subjects: Alzheimer’s disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Aspartic Acid Endopeptidases - antagonists & inhibitors; BACE1; BACE1 inhibitor; bioavailability; Biological and medical sciences; enzyme activity; Medical sciences; membrane permeability; Models, Molecular; Molecular Structure; Nitro Compounds - chemistry; Nitro Compounds - pharmacology; Peptide Hydrolases - chemical synthesis; Peptide Hydrolases - pharmacology; Pharmacology. Drug treatments; Phthalic Acids - chemistry; Phthalic Acids - pharmacology; Structure-Activity Relationship; structure-activity relationships; β-Secretase
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.05.089

Recently, we reported substrate-based pentapeptidic BACE1 inhibitors possessing a hydroxymethylcarbonyl isostere as a substrate transition-state mimic. These inhibitors showed potent inhibitory activities in enzymatic and cell assays. We also designed and synthesized non-peptidic and small-sized inhibitors possessing a heterocyclic scaffold at the P2 position. By studying the structure–activity relationship of these inhibitors, we found that the σ–π interaction of an inhibitor with the BACE1-Arg235 side chain played a key role in the inhibition mechanism. Hence, we optimized the inhibitors with a focus on their P2 regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position are described along with the results of the related structure–activity relationship study. These small-sized inhibitors are expected improved membrane permeability and bioavailability.