A patent review of glutaminyl cyclase inhibitors (2004–present)

ABSTRACT

Introduction: Glutaminyl cyclase (QC) enzymes catalyze the post-translational processing of several substrates with N-terminal glutamine or glutamate to form pyroglutamate (pE) residue. In addition to physiological functions, emerging evidence demonstrates that human QCs play a part in pathological processes in diverse diseases such as Alzheimer’s disease (AD), inflammatory and cancer diseases.

Areas covered: In recent years, efforts to effectively develop QC small-molecule inhibitors have been made and different chemical classes have been disclosed. This review summarizes the patents/applications regarding QC inhibitors released from 2004 (first patent) to now. The patents are mostly described in terms of chemical structures, biochemical/pharmacological activities, and potential clinical applications.

Expert opinion: For more than 15 years of research, the knowledge on the QC activity domain has considerably increased and therapeutic potential of QC inhibitors has been explored. An important number of studies and patents have been published to expand the use of QC inhibitors. QC enzymes are pharmacologically interesting targets to be used as an AD-modifying therapy, or for other QC-associated disorder. Distinct classes of chemical scaffolds and potential clinical uses have been claimed by various organizations. For the coming years, there is much to experience in the QC field.

KEYWORDS:

• Alzheimer’s disease (AD)
• cancer
• inflammation
• glutaminyl cyclase (QC)
• glutaminyl cyclase isoform (isoQC)
• pyroglutamate residue (pE)
• small-molecule inhibitors

Article highlights

• QC mediates the formation of pyroglutamate (pE) at the N-terminus of several substrates.

• QC activity plays a significant role in Alzheimer’s disease (AD), inflammatory, cancer and other diseases.

• The pyroglutamate-amyloid-β (pE-Aβ) formation is catalyzed by QC, which contributes to the AD pathology.

• The evidence of QC activity in AD made the enzyme a promising target for treating and preventing AD.

• Prevent the maturation of pE-chemokines by inhibiting QC activity might reduce inflammatory responses.

• IsoQC has recently been indicated as a target for cancer immunotherapy.

• Interest of QC inhibitors has been increased over the last years.

• Progress in the development of QC inhibitors patented since 2004 is reviewed.

• Varoglutamstat is a lead candidate and first-in-class inhibitor currently being evaluated in clinical trials for AD treatment.

• New therapeutic uses for QC inhibitors are being continuously discovered.

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 on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This work was supported by European Regional Development Fund (ERDF), through the Centro 2020 Regional Operational Programme under the project CENTRO-01-0247-FEDER-003269 (Drugs2CAD) and through COMPETE 2020 - Operational Programme for Competitiveness and Internationalization and Portuguese national funds via Portuguese Foundation for Science and Technology (FCT), under the project UIDB/04539/2020. The authors are grateful to University of Coimbra and Judite R.M. Coimbra thanks FCT for funding the individual PhD grant SFRH/BD/138460/2018.