Novel matrix metalloproteinase inhibitors: an updated patent review (2014 - 2020)

ABSTRACT

Introduction: Matrix MetalloProteinases (MMPs) are key enzymes in several pathophysiological processes connected to the extracellular matrix (ECM) degradation. Earlier clinical trials evaluating broad spectrum MMP inhibitors as cancer therapeutics failed to succeed, resulting in toxic side effects, such as musculoskeletal pain and inflammation, due to poor selectivity. As it is now recognized that some MMPs are essential for tumor progression and metastasis, but others play host-protective functions, selective MMP inhibitors are needed, and their interest has grown also for therapeutic applications beyond cancer, such as infectious, inflammatory and neurological diseases. Areas covered: This updated review describes patents concerning MMP inhibitors published within January 2014 and June 2020, with therapeutic applications spanning from cancer to inflammatory and neurological disorders. Expert opinion: Although the number of patents has decreased with respect to the previous decade, new applications provide selective matrix metalloproteinase inhibitors for therapeutic treatments beyond cancer. For several applications, the need of selective inhibitors resulted in the development of new non-hydroxamate compounds, paving the way towards a renewed interest towards MMPs as therapeutic targets. In particular, inhibitors able to cross the blood-brain barrier have been disclosed and proposed for the treatment of neurological conditions, infections, wound healing and cancer.

KEYWORDS:

• Angiogenesis
• articular cartilage
• cancer
• protease inhibitor
• zinc-binding group

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers in this manuscript have no relevant financial or other relationships to disclose.

Article highlights

• MMPs are key in several physiological processes connected to the extracellular matrix (ECM) degradation, including growth, wound healing and other functions for tissue reorganization, as well as pathological conditions with increased MMP activity.

• New patents on selective inhibitors against gelatinases, collagenases, membrane-type and elastase subgroups, released within January 2014 and July 2020 are herein summarized, reporting general formula structures and representative compounds claimed in each patent.

• Selectivity among closely related MMPs has been achieved by developing non-hydroxamate inhibitors with heterocyclic scaffolds as the zinc binding groups.

• A promising application of patented MMP inhibitors is the development of a molecular construct containing a chemical probe for molecular imaging studies to follow drug distribution and measure drug efficacy.

• The recent development of MMP inhibitors capable to cross the blood-brain barrier can be used for the treatment of neurological conditions and cancer.

Additional information

Funding

The authors acknowledge Ministero dell’Istruzione, dell’Università e della Ricerca (‘Progetto Dipartimenti di Eccellenza 2018-2022’ allocated to Department of Chemistry ‘Ugo Schiff’) and Fondazione Cassa di Risparmio di Pistoia e Pescia (Bando Giovani@Ricerca scientifica 2018) for financial support.