Inhibition of matrix metalloproteinases by hydroxamates containing heteroatom-based modifications of the P1' group.

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Gowravaram MR, Tomczuk BE, Johnson JS, Delecki D, Cook ER, Ghose AK, Mathiowetz AM, Spurlino JC, Rubin B, Smith DL, et al.

Inhibition of matrix metalloproteinases by hydroxamates containing heteroatom-based modifications of the P1' group.

J Med Chem. 1995 Jul 7;38(14):2570-81.

PubMed ID

7629797 [ View in PubMed

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Abstract

In this study, structure-based drug design of matrix metalloproteinase inhibitors [human fibroblast collagenase (HFC), human fibroblast stromelysin (HFS), and human neutrophil collagenase (HNC)] was utilized in the development of potent hydroxamates which contain novel, heteroatom-based modifications of the P1' group. A series containing a P1' butyramide group resulted in a nanomolar potent and selective HNC inhibitor as well as a dual HFS/HNC inhibitor. Benzylic ethers with a four- or five-carbon methylene linker in the P1' position also produced nanomolar potent HFS/HNC inhibition and micromolar potent HFC inhibition as expected. Surprisingly, the phenolic ethers of the same overall length as the benzylic ethers showed nanomolar potencies against HFC, as well as HFS and HNC. The potency profile of the phenolic ethers was optimized by structure-activity relationships of the phenolic group and the C-terminal amide. These inhibitors may help elucidate the in vivo roles of matrix metalloproteinases in normal and disease states.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
METHYLAMINO-PHENYLALANYL-LEUCYL-HYDROXAMIC ACID	Interstitial collagenase	Ki (nM)	7	N/A	N/A	Details
METHYLAMINO-PHENYLALANYL-LEUCYL-HYDROXAMIC ACID	Neutrophil collagenase	Ki (nM)	2	N/A	N/A	Details