1. The design, synthesis, and structure-activity relationships of a series of macrocyclic MMP inhibitors.
- Author
-
Steinman DH, Curtin ML, Garland RB, Davidsen SK, Heyman HR, Holms JH, Albert DH, Magoc TJ, Nagy IB, Marcotte PA, Li J, Morgan DW, Hutchins C, and Summers JB
- Subjects
- Crystallography, X-Ray, Drug Design, Humans, Hydroxamic Acids chemistry, Hydroxamic Acids pharmacology, Indicators and Reagents, Kinetics, Matrix Metalloproteinase 8, Models, Molecular, Phenylalanine chemistry, Phenylalanine pharmacology, Protease Inhibitors chemistry, Protease Inhibitors pharmacology, Structure-Activity Relationship, Succinates chemical synthesis, Succinates chemistry, Succinates pharmacology, Thiophenes pharmacology, Collagenases chemistry, Hydroxamic Acids chemical synthesis, Matrix Metalloproteinase Inhibitors, Phenylalanine analogs & derivatives, Protease Inhibitors chemical synthesis, Thiophenes chemical synthesis, Thiophenes chemistry
- Abstract
A series of succinate-derived hydroxamic acids incorporating a macrocyclic ring were designed, synthesized, and evaluated as inhibitors of matrix metalloproteinases. The inhibitors were designed based on the published X-ray crystal structure of batimastat (1) complexed with human neutrophil collagenase (MMP-8). The synthesized compounds were shown to inhibit selected MMPs in vitro with low nanomolar potency.
- Published
- 1998
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