page_title: Metalloprotease inhibitor
section_title: Pyrimidine-based inhibitors
hierarchical_section_title: Metalloprotease inhibitor / Drug development / Pyrimidine-based inhibitors
context_page_description: Metalloprotease inhibitors are cellular inhibitors of the Matrix metalloproteinases. MMPs belong to a family of zinc-dependent neutral endopeptidases. These enzymes have the ability to break down connective tissue. The expression of MMPs is increased in various pathological conditions like inflammatory conditions, metabolic bone disease, to cancer invasion, metastasis and angiogenesis.
  Examples of diseases are periodontitis, hepatitis, glomerulonephritis, atherosclerosis, emphysema, asthma, autoimmune disorders of skin and dermal photoaging, rheumatoid arthritis, osteoarthritis, multiple sclerosis, Alzheimer's disease, chronic ulcerations, uterine involution, corneal epithelial defects, bone resorption and tumor progression and metastasis. Due to the role of MMPs in pathological conditions, inhibitors of MMPs may have therapeutic potential. Several other proteins have similar inhibitory effects, however none as effective. They might have other biological activities which have yet been fully characterised.
  MMP inhibitors can broadly be subdivided into non-synthetic or synthetic.
context_section_description: Ro 28-2653 is highly selective for MMP-2, MMP-9 and membrane type 1 (MT-1)-MMP. It is an antitumor and antiangiogenic agent with oral bioavailability. Inhibition of TACE and MMP-1 are linked to the musculoskeletal side effects seen in hydroxamate metalloproteinase inhibitors, but this compound spares the enzymes. 
  It has been shown to diminish tumor growth in nasal cancer in rats as well as prostate cancer cell cultures. The compound only has moderate effect on mice's adipose tissue and no alteration on joints. Based on this, it is concluded that class of inhibitors is less likely to trigger neuromuscular adverse effects. On the active site of the structure is a pyrimidinetrione chelation and the phenyl and piperidynil section occupy the S1’ and S2’ binding pockets of MMP-8.
  Compound 556052-30-3 is similar to Ro 28-2653 but incorporates a 4-((2-methylquinolin-4-yl)methoxy)phenyl sidechain that is TACE selective. 
  5-(spiropyrrolidin-5-yl)pyrimidinetrione is a compound named 848773-43-3 that is a potent MMP-2, MMP-9 and MMP-13 inhibitor that spares MMP-1 and TACE. 
  By substituting 1,3,4-oxadiazol-2-yl heteroaryl at C-4’ of the diphenylether segment to accomplish MMP-13 selectivity over MT-1 MMP, made the compound 420121-84-2. The compound has IC₅₀ (half maximal inhibitory concentration) of 1 nM for MMP-13.
  I125-radioable pyrimidinetriones that have similar structure have been made to be used in MMP-9 elevated atherosclerosis and elevated MMP-2 and MMP-9 cancers. 
  This class of MMP inhibitors is easy to synthesize and are potent enough for clinical valuation. 
  Compound 544678-85 is the latest pyrimidine based inhibitor, the compound is a pyrimidine-4,6-dicarboxamide that is very potent and MMP-13 selective. The compound has a specificity loop that within the S1’ pocket and its 3-methyl-4-fluoro group is proximal enough to the zinc to change the water entity. These compounds have good oral bioavailability and properties that promote them to be a good candidate for a subtype inhibitor of MMP-13 based diseases and future development.
  Pyrimidine dicarboxamides are highly selective MMP-13 inhibitors. In the S1’ pocket of MMP-13 is an S1’ side pocket that is unique to the matrix metalloproteiase. Pyrimidine dicarboxamides bind to this side pocket, which increases the selectivity. The role of MMP-13 is cleaving fibrillar collagen at neutral pH and higher mRNA levels of MMP-13 is detected in breast carcinoma and osteoarthritis joints.
  The pyrimidine dicarboxamide inhibitor example in the image does not interact with the catalytic zinc ion but rather binds to the S1’ side pocket. One pyridyl arm is situated to the entrance of the S1’ pocket while the other pyridyl arm goes through the S1’ pocket into the side pocket.
caption: Pyrimidine dicarboxamide