Development of a putative Zn2+-chelating but highly selective MMP-13 inhibitor

Rita Fürst*, Jun Yong Choi, Anna M. Knapinska, Michael D. Cameron, Claudia Ruiz, Amber Delmas, Mark S. Sundrud, Gregg B. Fields*, William R. Roush*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Starting from an already known MMP-13 inhibitor, 1, we pursued an SAR-approach focusing on optimizing interactions close to the Zn2+ binding site of the enzyme. We found the oxetane containing compound 32 (MMP-13 IC50 = 42 nM), which exhibited complete inhibition of collagenolysis in in vitro studies and an excellent selectivity profile among the MMP family. Interestingly, docking studies propose that the oxetane ring in 32 is oriented towards the Zn2+ ion for chelating the metal ion. Chelating properties of MMP13-inhibitors are often connected with non-selectivity within the enzyme family. Compound 32 demonstrates a rare example where the selectivity can be explained via combinatorial effects of interactions within the S1′ loop and a chelating effect of the oxetane moiety. Furthermore, in vivo pharmacokinetic studies were performed demonstrating a concentration of 1.97 μM of 32 within the synovial fluid of the rat knee joint, which makes the compound a promising lead compound for further optimization and development for osteoarthritis.

Original languageEnglish
Article number129014
JournalBioorganic and Medicinal Chemistry Letters
Volume76
DOIs
Publication statusPublished - 15 Nov 2022

Keywords

  • Collagenolysis inhibition
  • In vitro and in vivo pharmacokinetics
  • Matrix metalloproteinase 13
  • Oxetane containing inhibitors
  • Structure–activity relationship

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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