1. Introduction 2. DPP-4 inhibitors-related patents from 2012 to 2014 3. Patents containing new chemical entities, organic syntheses and crystallization procedures 4. DPP-4 peptides inhibitors 5. Non-peptidomimetic inhibitors 6. Patent related to preparation and association with other drugs 7. Expert opinion Review DPP-4 inhibitors: a patent review (2012 -- 2014) Roberto Costante, Azzurra Stefanucci, Simone Carradori, Ettore Novellino & Adriano Mollica † † Universit  a di Chieti-Pescara “ G. d’ Annunzio” , Dipartimento di Farmacia, Chieti, Italy Introduction: Dipeptidyl peptidase 4 (DPP-4) is a serine protease, which catalyzes the hydrolytic process of the amide bond X-Ala or X-Pro at the N-terminus of peptides. This enzyme is involved in the degradation of two incretin hormones glucagon-like peptide-1 and glucose-dependent- insulinotropic polypeptide, which increase the production and release of insu- lin. Therefore, DPP-4 inhibitors are considered as one of the well-established therapies available for type 2 diabetes mellitus. Areas covered: In this review, the authors report all the patents related to DPP-4 inhibitors from 2012 to 2014. The chemical-related patents have been divided in three general families: i) peptidomimetics; ii) peptides; and iii) non-peptidomimetics compounds. The third group is the most consistent; thus the patents have been further divided on the basis of the chemical structure. In the last section, we briefly discuss the patents containing the formulations or associations of DPP-4 inhibitors with other drugs. Expert opinion: In the last few years, the research on DPP-4 inhibitors has significantly grown leading to the development of heterocyclic scaffolds and non-peptidomimetic structures. Unfortunately, these compounds are not immune from side effects associated with the inhibition of other substrates, indicating that DPP-4 inhibitors are likely multi-target drugs. Therefore, their potential multi-target effects require more attention in clinical practice, even if at this moment, all the patents are focused only on diabetes. Keywords: CD26, dipeptidyl peptidase 4 inhibitors, incretin system, type 2 diabetes mellitus Expert Opin. Ther. Patents (2015) 25(2):209-236 1. Introduction Dipeptidyl peptidase 4 (DPP-4) is a proteolytic enzyme that processes the amide bond X-Ala or X-Pro at the N-terminus of a peptide (Figure 1). Almost all human organs express the enzyme DPP-4 [1]. Indeed, DPP-4 is involved in the proteolytic degradation of two incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent-insulinotropic polypeptide (GIP), which are responsible for the increasing of the production and release of insulin by promoting the activity and the health of the pancreatic b-cells. DPP-4 inhibitors are now considered as one of the well-established therapies available for diabetes mellitus type 2 (T2DM): in addition to the well-known anti-hyperglycemic and pancreatic islet protective effects, other effects of novel DPP-4 inhibitors have been observed, such as immune regulation [2-5], cardiovascular protection [6-10] and anti-inflammatory effects [11-14]. Recently, side effects of DPP-4 inhibitors have been reported including hemoly- sis [15], leucopenia [16], angioedema [17-19], and rheumatoid arthritis, [20], which are possibly associated with the inhibition of other substrates, indicating a multi-target potentiality. Therefore, their potential multi-target effects are likely to gain more attention in clinical practice [21,22]. 10.1517/13543776.2014.991309 © 2015 Informa UK, Ltd. ISSN 1354-3776, e-ISSN 1744-7674 209 All rights reserved: reproduction in whole or in part not permitted Expert Opin. Ther. Patents Downloaded from informahealthcare.com by Dr Claudiu T. Supuran on 01/21/15 For personal use only.