Drugs in development: bisphosphonates and metalloproteinase inhibitors

Abstract

The destruction of bone and cartilage is characteristic of the progression of musculoskeletal diseases. The present review discusses the developments made with two different classes of drugs, the bisphosphonates and matrix metalloproteinase inhibitors. Bisphosphonates have proven to be an effective and safe treatment for the prevention of bone loss, especially in osteoporotic disease, and may have a role in the treatment of arthritic diseases. The development of matrix metalloproteinase inhibitors and their role as potential therapies are also discussed, especially in the light of the disappointing human trials data so far published.

Figure 1

Structure of pyrophosphate and a generic bisphosphonate.

Figure 2

Structures of the R1 and R2 side chains (see Fig. 1) of bisphosphonates investigated in humans. The bisphosphonates are grouped according to their potency for inhibiting bone resorption in rats.

Figure 3

Schematic showing the mevalonate pathway. Nitrogen-containing bisphosphonates inhibit the farnesyl diphosphate synthase enzyme, which prevents the production of farnesyl diphosphate that is required for protein prenylation. Inhibition of protein prenylation leads to loss of association of GTP-binding proteins with the cell surface and to a breakdown in intracellular signalling.

Figure 4

Control steps for matrix degradation by matrix metalloproteinases (MMPs). Cells are initially stimulated by proinflammatory cytokines through cell surface receptors. These receptors then transfer the signal to the nucleus via a series of signal transduction pathways leading to mRNA upregulation. The MMP is synthesised and secreted in an inactive proform and requires activation by enzymic cleavage of the prodomain. Cells also produce natural inhibitors of MMPs, called tissue inhibitor of metalloproteinases (TIMPs), that inhibit the activated MMPs. Uncontrolled matrix degradation only occurs when the balance between the TIMP and the active MMP shifts in favour of degradation. MT, membrane type; TNFα, tumour necrosis factor alpha.

Figure 5

Matrix metalloproteinase (MMP) inhibitor interactions. Subsites around the catalytic zinc (Zn) bind amino acids in the substrate on either side of the cleavage site. Synthetic MMP inhibitors use a zinc binding group (ZnBG) attached to modified peptides that can bind tightly to these subsites. LHS, left-hand side; P, position of residues in the peptide; RHS, right-hand side; S, subsites of the active site.