Novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P2 position.
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 P(2) 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 P(2) regions. In this Letter, a series of novel BACE1 inhibitors possessing a 5-nitroisophthalic scaffold at the P(2) 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.
Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Minatojima, Chuo-ku, Kobe 650-8586, Japan.
Yoshio
Y
Hamada
Tomoya
T
Nakanishi
Kenji
K
Suzuki
Ryoji
R
Yamaguchi
Takashi
T
Hamada
Koushi
K
Hidaka
Shoichi
S
Ishiura
Yoshiaki
Y
Kiso
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D008958:Models, Molecular; D015394:Molecular Structure; D009574:Nitro Compounds / Q000737:chemistry* / Q000494:pharmacology; D010447:Peptide Hydrolases / Q000138:chemical synthesis* / Q000494:pharmacology; D010795:Phthalic Acids / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D009574:Nitro Compounds; D010795:Phthalic Acids; C032279:phthalic acid; D053829:Amyloid Precursor Protein Secretases; D010447:Peptide Hydrolases; D016282:Aspartic Acid Endopeptidases