Synthesis and preliminary evaluation of peptidomimetic inhibitors of human beta-secretase.
Based on the structure of OM99-2 and the X-ray crystal structure of its complex with beta-secretase, a series of compounds containing the Leu*Ala hydroxyethylene isostere as a scissile bond substitution were designed. 31 compounds were synthesized and their beta-secretase inhibition activities were measured. It was found that isobutyl group was a better R3 substitution as C-terminus in our target compounds, and 4-nitrobenzyl group was the best R2 side chain. With the aid of molecular modeling, the binding modes of compounds 9 and 22 with beta-secretase were compared. The result revealed a stronger bonding mode of 22 than 9. This explored that the optimal length of this series of peptidomimetic inhibitors was P3-P2'. The molecular weights of compounds with this length are around 600.
Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Peking University, Beijing 100191, PR China.
Yan
Y
Niu
Yuehua
Y
Wang
Xiaomin
X
Zou
Xiaoming
X
Yang
Chao
C
Ma
Yang
Y
Lü
Bo
B
Zhou
Yue
Y
Yuan
Guanhua
G
Du
Ping
P
Xu
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005030:Ethylenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D005030:Ethylenes; C067254:hydroxyethylene; D053829:Amyloid Precursor Protein Secretases