Dipeptidyl peptidase IV inhibitors as a potential target for diabetes: patent review (2015-2018)

ABSTRACT

Introduction: Dipeptidyl peptidase 4 (DPP-4) belongs to the family of serine proteases and is involved in the degradation of GLP-1 and GIP hormones, which enhance the production and release of insulin. Targeting DPP-4 inhibitors is increasingly being considered as promising paradigms to treat type 2 diabetes mellitus and therefore DPP-4 inhibitors are being considered as promising antidiabetic drugs.

Areas covered: This review provides an overview of published patents describing natural and synthetic DPP-4 inhibitors from January 2015 to December 2018.

Expert opinion: A fair number of new synthetic and natural DPP-4 inhibitors have been reported in the last four years which describe the progress in the development of various heterocyclic scaffolds or heterocyclic hybrid compounds. As a result of this, many marketed DPP-4 inhibitors that have been approved by the appropriate governing bodies during the past decade, have been introduced as inhibitors. Molecular hybridization is an emerging idea in medicinal chemistry and therefore hybrid compounds of DPP-4 inhibitors with other DPP-4 inhibitors or with antidiabetic drugs should be formulated for a comprehensive evaluation. More detailed pharmacovigilance of DPP-4 inhibitors is required because this will address the pancreas-related adverse events as well as their impact on cardiovascular outcomes via long-term studies.

KEYWORDS:

• DPP-4
• synthetic inhibitor
• natural inhibitor
• diabetes

Article highlights

• DPP-4 inhibitors have been considered as promising antidiabetic drugs.

• This review outlines the synthetic and natural DPP-4 inhibitors.

• Compounds in this review mostly possess potent DPP-4 inhibitory effects in the low nanomolar range of IC₅₀ values.

• Various hybrid compounds were prepared comprising heterocyclic scaffolds and showed significant DPP-4 inhibition.

• Modifying heterocyclic compounds with flourine, methoxyethanesulfonyl, dimethylcarbamoyl, imidazole, amide, cyanide, and CF₃ groups greatly enhance their DPP-4 inhibitory effects.

• Several DPP-4 inhibitors have been evaluated in clinical trials.

• Computer Aided Drug Design (CADD) strategies should be used to a much greater extent in DPP-4 drug discovery.

This box summarizes the key points contained in the article.

Acknowledgments

H Hussain is thankful to Alexander von Humboldt Foundation for its generous support in providing the opportunity to do work in Germany which facilitated the writing of this review.

Author contributions

This review paper is mainly scripted and conceptualized by H Hussain and G Abbas, who contributed to the technical detail compilation and references, language proficiency and formatting of the manuscript. IR Green proofread the manuscript, critically checked the manuscript, and also contributed to the checking of language proficiency. I Ali contributed in the organization of contents, drawing the structures for the review paper and in the revision of the manuscript.

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 paper was not funded.