Design of non-peptide inhibitors based on structure analyses of the protease/inhibitor complex

2015 Fiscal Year Final Research Report

• Project/Area Number: 25460160
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Drug development chemistry
• Research Institution: Kyoto Pharmaceutical University
• Principal Investigator: Akaji Kenichi 京都薬科大学, 薬学部, 教授 (60142296)
• Co-Investigator(Renkei-kenkyūsha): HATTORI Yasunao 京都薬科大学, 薬学部, 助教 (20567028)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: プロテアーゼ / 阻害剤 / 疎水性相互作用 / 複合体構造解析 / 縮環構造

Outline of Final Research Achievements

Evaluation of a novel decahydroisoquinolin scaffold as an inhibitor for severe acute respiratory syndrome (SARS) chymotrypsin-like protease (3CLpro) was achieved. Focusing on hydrophobic interactions at the S2 site, the decahydroisoquinolin scaffold was designed by connecting the P2 site group to the main-chain nitrogen atom of the P2 position via a methylene linker. All decahydroisoquinolin inhibitors synthesized showed moderate but clear inhibitory activities for SARS 3CLpro, which confirmed the fused ring structure functions as a novel scaffold for SARS 3CLpro inhibitor.
Hydroxyethylamine (HEA) isostere, as a transition state mimic, was incorporated into macro-cyclic structures connecting the P2 and P4 site of the substrate sequence of BACE1, a key protease for the onset of Alzheimer diseases. Synthesized cyclic inhibitor showed moderate but clear inhibitory activity for BACE1, which confirmed the ring structure functions as a novel scaffold for BACE1 inhibitor.

Free Research Field

医薬品化学