SEARCHING FOR SELECTIVE INHIBITORS OF MATRIX METALLOPROTEINASE TYPE 2 IN A SERIES OF BENZOYLAMINO (PHENYLSULFONYL)-SUBSTITUTED CYCLIC AMINO ACID DERIVATIVES

DOI: https://doi.org/10.29296/25877313-2020-11-04
Issue: 
11
Year: 
2020

O.S. Grigorkevich Junior Research Scientist, Zakusov Institute of Pharmacology (Moscow) G.V. Mokrov Ph.D. (Chem.), Zakusov Institute of Pharmacology (Moscow) N.N. Zolotov Dr.Sc. (Biol.), Professor, Zakusov Institute of Pharmacology (Moscow) V.V. Barchukov Research Scientist, Zakusov Institute of Pharmacology (Moscow) S.A. Kryzhanovskii Dr.Sc (Med.), Zakusov Institute of Pharmacology (Moscow) T.A. Gudasheva Dr.Sc. (Biol.), Professor, Corresponding Member of the RAS, Zakusov Institute of Pharmacology (Moscow)

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-NH2 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 1-{4-[(4-chlorobenzoyl)amino]phenyl}sulfonyl-L-proline (code AL-828) and 1-{4-[(2-chlorobenzoyl)-amino]phenyl}sulfonyl-L-proline (code ML-269) are selective MMP-2 inhibitors with inhibition constants 45±8,5 µМ and 82,5±17,2 µМ, 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.

Keywords: 
1-{4-[(2-chlorobenzoyl)amino]phenyl}sulfonyl-L-proline
1-{4-[(4-chlorobenzoyl)amino] phenyl}sulfonyl-L-proline
AL-828
ML-869
MMP-2
inhibitor
acute myocardial ischemia

References: 
  1. Vsemirnaja organizacija zdravoohranenija: [sajt]. URL: https://www.who.int/ru/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) (data obrashhenija 28.02.2020).
  2. Spinale F.G. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function. Physiol. Rev. 2007; 87: 1285 1342.
  3. Simova J., Skvor J., Slovak D., et al. Serum Levels of Matrix Metalloproteinases 2 and 9 in Patients with Acute Myocardial Infarction. Folia Biol. 2013; 59: 181–187.
  4. Hori M., Nishida K. Oxidative stress and left ventricular remodelling after myocardial infarction. Cardiovasc. Res. 2009; 81(3): 457–464.
  5. Creemers E., Cleutjens J., Smits J., et al. Matrix Metallo-proteinase Inhibition After Myocardial Infarction: A New Approach to Prevent Heart Failure? Circ Res. 2001; 89: 201–210.
  6. Laronha H., Carpinteiro I., Portugal J., et al. Challenges in Matrix Metalloproteinases Inhibition. Biomolecules. 2020; 10 (5); 717.
  7. Grigorkevich O.S., Mokrov G.V., Djabina A.S. i dr. Dizajn, sintez i farmakologicheskaja aktivnost' novogo ingibitora matriksnoj metalloproteinazy-9. Himiko-farmacevticheskij zhurnal. 2018; 52(1): 8–14.
  8. Seredenin S.B., Mokrov G.V., Kryzhanovskij S.A., Lihosherstov A.M. i dr. Ingibitory cink-zavisimyh metalloproteinaz (MMP-2 i MMP-9) v rjadu benzoilamino(fenilsul'fonil)-zameshhennyh ciklicheskih aminokislot kak potencial'nye lekarstvennye sredstva, prepjatstvujushhie postinfarktnomu remodelirovaniju levogo zheludochka serdca. Patent RF № 2646752. 2016.
  9. Faust A. Waschkau B., Waldeck J., et al. Synthesis and Evaluation of a Novel Fluorescent Photoprobe for Imaging Matrix Metalloproteinases. Bioconjugate Chem. 2008; 19: 1001–1008.
  10. Cerisano G., Buonamici P., Gori A.M., et al. Matrix metalloproteinases and their tissue inhibitor after reperfused ST-elevation myocardial infarction treated with doxycycline. Insights from the TIPTOP trial. Int. J. Cardiol. 2015; 197: 147–153.