THE SCRIPPS RESEARCH INSITUTE (T.S.R.I.);FLORIDA ATLANTIC UNIVERSITY BOARD OF TRUSTEES
发明人:
ROUSH, WILLIAM R.,CHOI, JUN YONG,FUERST, RITA,FIELDS, GREGG B.
申请号：
CA3066357
公开号：
CA3066357A1
申请日:
2018.06.06
申请国别(地区):
CA
年份:
2018
代理人:
摘要：
We describe the use of comparative structural analysis and structure-guided molecular design to develop potent and selective inhibitors (10d and (S)-17b) of matrix metalloproteinase 13 (MMP-13). We applied a three-step process, starting with a comparative analysis of the X-ray crystallographic structure of compound 5 in complex with MMP-13 with published structures of known MMP-13inhibitor complexes followed by molecular design and synthesis of potent, but non-selective zinc-chelating MMP inhibitors (e.g., 10a and 10b). After demonstrating that the pharmacophores of the chelating inhibitors (S)-10a, (R)-10a, and 10b were binding within the MMP-13 active site, the Zn2+ chelating unit was replaced with non-chelating polar residues that bridged over the Zn2+ binding site and reach into a solvent accessible area. After two rounds of structural optimization, these design approaches led to small molecule MMP-13 inhibitors 10d and (S)-17b which bind within the substrate-binding site of MMP-13 and surround the catalytically active Zn2+ ion without chelating to the metal. These compounds exhibit at least 500-fold selectivity versus other MMPs.
