# SYNTHETIC COLLAGENASE INHIBITORS

> **NIH NIH R01** · UNIVERSITY OF LOUISVILLE · 1990 · $142,603

## Abstract

The long term objective of this research is to prepare inhibitors of
collagenase and other metalloenzymes that degrade the
macromolecules of the extracellular matrix and to develop these
inhibitors into therapeutically useful drugs for the treatment of
disease such as rheumatoid and osteoarthritis in which these
molecules are broken down at an excessive rate.  Other conditions
in which such inhibitors might be therapeutically useful are
periodontal disease, corneal ulceration and recessive dystrophic
epidermolysis bullosa.  In addition, collagenases have been
implicated in tumor cell metastasis, ovulation, angiogenesis, and
other processes requiring cells to overcome barriers to migration.
In this application, we propose to use collagenase inhibitors that
we have already prepared which are effective in vivo at
nanomolar concentrations to characterize collagenases and other
metalloproteinases at the molecular level, to characterize some
of the pharmacological properties of these inhibitors, and to
generate new peptide inhibitors of improved potency, specificity,
and pharmacological properties.

In keeping with these broad goals, the specific aims of the project
are:  first, purification of collagenases from pig synovial
membranes, neutrophil granules and a human monocyte cell line
using affinity techniques that we have developed; irreversible
labelling of the active site of these collagenases using inhibitor
derivatives and determination of the amino acid sequence of the
active site peptides for comparison with other well-characterized
zinc proteinases; and investigation of inhibitor specificity with
these enzymes.  Second, design and synthesis of new peptide
inhibitors using conformational analysis, x-ray crystallography and
computer graphics techniques coupled both with potency data for
currently available compounds as well as newly acquired
structure-function data; preparation and evaluation of
coordinating amide bond replacements as a new class of
collagenase inhibitor.  Our third specific aim is determination of
inhibitor stability in blood, plasma and tissue homogenates, and in
an in vitro model of inflammatory disease using activated
macrophages to simulate the in vivo environment of the inhibitor;
determination in the mouse of the pharmacokinetic, tissue
distribution and biotransformation of one or more collagenase
inhibitors in hand as well as any new derivatives with improved
properties that may be developed.

## Key facts

- **NIH application ID:** 3159713
- **Project number:** 5R01AR039573-03
- **Recipient organization:** UNIVERSITY OF LOUISVILLE
- **SAM.gov UEI:** E1KJM4T54MK6
- **Principal Investigator:** ROBERT D GRAY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1990
- **Award amount:** $142,603
- **Award type:** 5
- **Project period:** 1988-07-01 → 1991-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/3159713

## Citation

> US National Institutes of Health, RePORTER application 3159713, SYNTHETIC COLLAGENASE INHIBITORS (5R01AR039573-03). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/3159713. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*