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2005
Barbituric acid derivatives
R 0530
Structure-Based Design of Potent and Selective Inhibitors of Collagenase-3
— Barbituric acid based inhibitors are considered as an interesting alter26- 096 (MMP-13).
native to hydroxamic acid based inhibitors. The use of a barbiturate as a zinc ligand
seems to be reasonable for the computer-aided drug design of a potent and selective
inhibitor of MMP-13. MMP-13 structural information, together with AM1 calculation
of the zinc-barbiturate interaction furnish the initial constrained lead (VIa). Once (VIa)
is synthesized and determined as a potent inhibitor of MMP-13, a flexible synthetic
route permits late-stage diversification of the terminal aryl group. Spiro-barbiturates
(VIb) and (XIIb) possess a similar potency and improved MMP-3 selectivity compared
to the hydroxamic acid based reference inhibitor, but significant selectivity against the
MMP-2 and MMP-9 is not achieved. — (KIM*, S.-H.; PUDZIANOWSKI, A. T.;
LEAVITT, K. J.; BARBOSA, J.; MCDONNELL, P. A.; METZLER, W. J.; RANKIN,
B. M.; LIU, R.; VACCARO, W.; PITTS, W.; Bioorg. Med. Chem. Lett. 15 (2005) 4,
1101-1106; Bristol-Myers Squibb Pharm. Res. Inst., Princeton, NJ 08543, USA;
Eng.) — H. Hoennerscheid
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