Searching for selective inhibitors of matrix metalloproteinase type 2 in a series of benzoylamino (phenylsulfonyl)-substituted cyclic amino acid derivatives

Relevance. Matrix metalloproteinases type 2 and 9 (MMP-2, MMP-9) initiate collagen degradation of the extracellular myocardial matrix in acute infarction which is accompanied by their release into the systemic circulation. MMP inhibitors are known to reduce post-infarction remodeling of the left ventricle of the heart. Effective cardiotropic drugs can be created based on them. Aim. Searching for selective matrix metalloproteinase type 2 inhibitors among benzoylamino(phenylsulfonyl)-substituted cyclic amino acid derivatives. Material and methods. Potential inhibitors were designed and synthesized earlier in the Zakusov Institute of Pharmacology. Inhibition constants were determined fluorimetrically using a substrate Mca-Lys-Pro-Leu-Gly-Leu-Dpa-Ala-Arg-Nhh and recombinant, active human MMP-2 and MMP-9. Effect of the most active inhibitors on the level of MMP-2 in the rat blood plasma with acute myocardial infarction (AMI) was determined in outbred male rats. AMI was reproduced by ligation of the coronary artery. The level of MMP-2 was determined by enzyme immunoassay. Results. It was shown that l-{4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl-L-proline (code AL-828) and l-{4-[(2-chlorobenzoyl)-amino]phenyl}sulfonyl-L-proline (code ML-269) are selective MMP-2 inhibitors with inhibition constants 45±8,5 pM and 82,5±17,2 pM, respectively. Compounds AL-828 and ML-269 reduce the level of MMP-2 in the blood plasma of rats with AMI in the doses of 30 mg/kg/day per os by 9% and 19% with p=0.08 and p=0.007, respectively, and, at least, are not inferior in their activity to the comparison drug doxycycline (40 mg/kg/day). Conclusion. Selective inhibitors of MMP-2, compounds ML-269 and AL-828, which can become the basis for the creation of cardioprotective drugs that prevent pathological post-infarction remodeling of the left ventricle of the heart were revealed.

l-{4-[(2-chlorobenzoyl)aminoJphenyl}sulfonyl-L-proline, l-{4-[(4-chlorobenzoyl)amino] phenyl}sulfonyl-L-proline, AL-828, ML-869, MMP-2, inhibitor, acute myocardial ischemia