Mechanism of action: Matrix metalloproteinase 9 & 12 (MMP9,12) inhibitor

Preclinical pharmacology

AZD1236 is a potent and reversible inhibitor of human MMP9 and MMP12 (IC50 = 4.5 and 6.1nM, respectively), with 10-15-fold selectivity to MMP2 and MMP13 and >350-fold selectivity to other members of the enzyme family. Its activity is approximately 20 to 50-fold lower at the rat, mouse, and guinea pig orthologues. In acute models of lung injury, AZD1236 inhibited the hemorrhage and inflammation induced by instillation of human MMP12 into rat lungs by ~80% at 0.81mg/kg, and also abolished macrophage infiltration into BAL fluid induced by tobacco smoke inhalation in the mouse.

Safety and tolerability

AZD1236 has been administered orally to healthy volunteers (in single doses up to 1500mg and multiple doses up to 500mg QD for 13 days) and COPD patients with moderate to severe disease (at 75mg BID for 6 weeks). The majority of adverse events were of mild intensity and resolved within the study peroid.

Pre-clinical toxicology studies of up to 12 month duration have been performed. Toxicologically important findings mainly relate to chronic treatment and included: diffuse eye lens opacities after 6 months administration to rats and fibrodysplasia in the subcutis after 12 months to dogs.

Clinical pharmacology

Target coverage data to date have been mixed. In healthy subjects, single dose of 30 or 75mg inhibited ex vivo zymosan-stimmulated whole blood MMP activity (the 75mg dose yielding plasma compound levels at Cmax steady state of ~120 x IC50). In contrast, 75mg BID for 6 weeks in COPD patients compared to placebo did not identify any significant change in whole blood MMP activity.

Suitable for and exclusions

The reproductive toxicology package indicates a risk of foetal toxicity. The inclusion of women of child-bearing potential would need to be assessed for any proposal based on the risk-benefit and the use of appropriate highly effective contraception.

The risk of muscular skeletal syndrome (MSS; joint fibrodysplasia), while reversible, has been seen after chronic administration with other MPP inhibitors in humans and fibrodyplasia in the subcutis has been seen at high doses in the 12 month preclinical safety study with AZD1236. This risk must be considered when proposing a new indication and proposed treatment should be less than 6 weeks in duration.

Additional Information

Clinical trials for this compound

See all of the clinical trials currently associated with this compound:

Publications for this compound

Find out more about this compound by reading related publications:

Effects of an oral MMP-9 and -12 inhibitor, AZD1236, on biomarkers in moderate/severe COPD: a randomised controlled trial

Safety and tolerability of an oral MMP-9 and -12 inhibitor, AZD1236, in patients with moderate-to-severe COPD: a randomised controlled 6-week trial

Gene information from the NCBi

This compound works on the following genes: