Abstract:Approved and potent reported dipeptidyl peptidase-4 (DPP-4) inhibitors with gliptin-like structures are classified here according to their structures and mechanisms of the inhibition in three groups: (i) those with pyrrolidine or analogs as P1 fragment with α-aminoacyl linker, (ii) structures with trifluorophenyl moiety or analogs as P1 fragment with β-aminobutanoyl linker, and (iii) DPP-4 inhibitors with pyrimidine-2,4-dione or analogs as P1′ fragment. The structure−activity relationship analysis was performe… Show more
“…Pyrrolidine 7sa, generated from pyrroline 4sa, can be further derivatized into the analogue of vildagliptin, which is used to treat type 2 diabetes (Scheme 4C). 2,4 Through N-acylation with the α-chloro acetyl chloride of 7sa, followed by nucleophilic substitution of alkyl chloride 9sa with 3-amino-1-adamantanol, vildagliptin analogue 10sa was afforded in a two-step sequence with a total yield of 40%. Given the ongoing challenge of identifying small molecules with high selectivity as dipeptidyl peptidase-4 (DPP-4) inhibitors, this study has the potential to provide a valuable contribution to the field of drug discovery centered on DPP-4 inhibitors.…”
Chiral 1-pyrrolines containing a nitrile motif serve as crucial structural scaffolds in biologically active molecules and exhibit diversity as building blocks owing to their valuable functional groups; however, the asymmetric synthesis of such compounds remains largely unexplored. Herein, we present an enantio-and diastereoselective method for the synthesis of α-chiral nitrilecontaining 1-pyrroline derivatives bearing vicinal stereocenters through the design and introduction of chiral cyclopropeniminebased bifunctional catalysts featuring a thiourea moiety. This synthesis entails a highly stereoselective conjugate addition of αiminonitriles to a wide array of enones, followed by cyclocondensation, thereby affording a series of cyanopyrroline derivatives, some of which contain all-carbon quaternary centers. Moreover, we demonstrate the synthetic utility of this strategy by performing a gramscale reaction with 1% catalyst loading, along with a variety of chemoselective transformations of the product, including the synthesis of a vildagliptin analogue. Finally, we showcase the selective synthesis of all four stereoisomers of the cyanopyrroline products through trans-to-cis isomerization, highlighting the versatility of our approach.
“…Pyrrolidine 7sa, generated from pyrroline 4sa, can be further derivatized into the analogue of vildagliptin, which is used to treat type 2 diabetes (Scheme 4C). 2,4 Through N-acylation with the α-chloro acetyl chloride of 7sa, followed by nucleophilic substitution of alkyl chloride 9sa with 3-amino-1-adamantanol, vildagliptin analogue 10sa was afforded in a two-step sequence with a total yield of 40%. Given the ongoing challenge of identifying small molecules with high selectivity as dipeptidyl peptidase-4 (DPP-4) inhibitors, this study has the potential to provide a valuable contribution to the field of drug discovery centered on DPP-4 inhibitors.…”
Chiral 1-pyrrolines containing a nitrile motif serve as crucial structural scaffolds in biologically active molecules and exhibit diversity as building blocks owing to their valuable functional groups; however, the asymmetric synthesis of such compounds remains largely unexplored. Herein, we present an enantio-and diastereoselective method for the synthesis of α-chiral nitrilecontaining 1-pyrroline derivatives bearing vicinal stereocenters through the design and introduction of chiral cyclopropeniminebased bifunctional catalysts featuring a thiourea moiety. This synthesis entails a highly stereoselective conjugate addition of αiminonitriles to a wide array of enones, followed by cyclocondensation, thereby affording a series of cyanopyrroline derivatives, some of which contain all-carbon quaternary centers. Moreover, we demonstrate the synthetic utility of this strategy by performing a gramscale reaction with 1% catalyst loading, along with a variety of chemoselective transformations of the product, including the synthesis of a vildagliptin analogue. Finally, we showcase the selective synthesis of all four stereoisomers of the cyanopyrroline products through trans-to-cis isomerization, highlighting the versatility of our approach.
“…Literature survey was performed to understand the history and chemistry of gliptins, the new oral antidiabetic agents, which were discovered for being DPP-4Is, from these approved DPP-4Is; sitagliptin, vildagliptin, saxagliptin, alogliptin and anagliptin, ( Fig.1 ) . Yet, to understand the chemistry and mode of action of gliptins, the structure of DPP-4 and its substrates should be mentioned and studied [21] , [22] . Fig.…”
Section: Resultsmentioning
confidence: 99%
“…Gliptin-like structure as sitagliptin, vildagliptin, saxagliptin, alogliptin and anagliptin, approved DPP-4Is ( Fig. 1 ), can be classified referring to their structures and enzyme inhibition mechanism into three main groups [21] . First, those with (i) pyrrolidine or analogues with α-aminoacyl linker to S1 subunit of the enzyme & P1 residues of substrates; as (vildagliptin, saxagliptin and teneligliptin).…”
“…46 Recently, Tomovic et al performed a structure− activity relationship (SAR) analysis of DPP-4 inhibitors, which were classified into three groups according to their structures and inhibition mechanisms. 47 In contrast to these articles, this Perspective comprehensively summarizes the development of long-acting DPP-4 inhibitors, highlighting the process of evolution from initial lead compounds to clinical candidates over nearly three decades. Next, we examine the determinants of a long duration of action, including the nature of the target, potency, binding kinetics, crystal structures, selectivity,…”
Section: Introductionmentioning
confidence: 99%
“…Over the past decade, many perspectives and reviews of DPP-4 inhibitors have been published, most of which focus on classifying DPP-4 inhibitors into several small pieces and listing the corresponding activity and selectivity and their pharmacokinetic properties. − Several reviews have specifically addressed the clinical use of DPP-4 inhibitors in treating T2DM, , DPP-4 inhibitors in clinical trials, , patent analysis, − and activity and selectivity cliffs for DPP-4 inhibitors . Recently, Tomovic et al performed a structure–activity relationship (SAR) analysis of DPP-4 inhibitors, which were classified into three groups according to their structures and inhibition mechanisms . In contrast to these articles, this Perspective comprehensively summarizes the development of long-acting DPP-4 inhibitors, highlighting the process of evolution from initial lead compounds to clinical candidates over nearly three decades.…”
Considerable effort has been made to achieve less frequent dosing in the development of DPP-4 inhibitors. Enthusiasm for long-acting DPP-4 inhibitors is based on the promise that such agents with less frequent dosing regimens are associated with improved patient adherence, but the rational design of long-acting DPP-4 inhibitors remains a major challenge. In this Perspective, the development of longacting DPP-4 inhibitors is comprehensively summarized to highlight the evolution of initial lead compounds on the path toward developing long-acting DPP-4 inhibitors over nearly three decades. The determinants for long duration of action are then examined, including the nature of the target, potency, binding kinetics, crystal structures, selectivity, and preclinical and clinical pharmacokinetic and pharmacodynamic profiles. More importantly, several possible approaches for the rational design of long-acting drugs are discussed. We hope that this information will facilitate the design and development of safer and more effective long-acting DPP-4 inhibitors and other oral drugs.
■ SIGNIFICANCE• The evolution of initial lead compounds on the path toward developing long-acting DPP-4 inhibitors over nearly three decades is reviewed. • The determinants for long duration of action are examined, including the nature of the target, potency, binding kinetics, crystal structures, selectivity, and preclinical and clinical PK and PD profiles. • Possible approaches for the rational design of longacting drugs are discussed.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
