Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors

Pissarnitski, Dmitri; Zhao, Zhiqiang; Cole, David; Wu, Wen‐Lian; Domalski, Martin S.; Clader, John W.; Scapin, Giovanna; Voigt, Johannes H.; Soriano, Aileen; Kelly, Theresa M.; Powles, Mary Ann; Yao, Zuliang; Burnett, Duane A.

doi:10.1016/j.bmc.2016.09.007

Cited by 12 publications

(8 citation statements)

References 35 publications

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“…Overall, at least nine compounds interacted with the residues in the DPP4 active sites; these have been reported in previous studies [1,[10][11][12][13][14], and eight of them have been predicted to be more selective toward DPP4 because they have interactions with the S1' subsite. The remaining three compounds with the lowest binding affinities (miraxanthin-i, ii, and v) do not appear to interact with the residues in the active sites of DPP4 (Table 2 and Fig.…”

Section: Molecular Dockingsupporting

confidence: 61%

In Silico Approach for Screening of the Indonesian Medicinal Plants Database to Discover Potential Dipeptidyl Peptidase-4 Inhibitors

2020

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Background: Dipeptidyl peptidase-4 (DPP4) is an enzyme responsible for inactivating the hormone incretin, which potentiates insulin secretion andglucagon inhibition; inhibitors of DPP4 are used as therapeutic drugs for type-2 diabetes.Objective: In this study, we evaluated potential DPP4 inhibitors from the Indonesian Medicinal Plants Database using an in silico approach.Methods: A ligand-based pharmacophore model was used for screening the database using LigandScout 4.2. This model was validated using severalparameters of enrichment metrics, including receiver operating characteristics, area under curve (AUC), and enrichment factor (EF). Hit compoundswere also docked with DPP4 to calculate the free binding energy and analyze the interaction between the ligand and DPP4. In addition, bioavailabilityand medicinal chemistry predictions were performed for the hit compounds.Results: The best pharmacophore model demonstrated AUC100% and EF1% values of 0.82 and 33.8, respectively. The pharmacophore features of themodel included hydrogen bond donors, hydrogen bonds, hydrophobic interactions, and positive ionization areas. Based on our results of virtualscreening and molecular docking, six hit compounds were ultimately identified, namely, L-noradrenaline, octopamine, Nb-demethylechitamine, alliin,isoalliin, and subaphylline.Conclusion: Collectively, our findings indicate that subaphylline is the most promising compound for further studies, including in vitro and in vivoexperiments and those focused on molecular dynamics and structural modification.

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Section: Molecular Dockingsupporting

confidence: 61%

In Silico Approach for Screening of the Indonesian Medicinal Plants Database to Discover Potential Dipeptidyl Peptidase-4 Inhibitors

2020

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“…117 Compound 49 achieved subnanomolar potency (IC 50 = 0.4 nM) and demonstrated oral activity in vivo in the mouse glucose tolerance test. 117 Compound 50, with a 2-cyanobenzyl replacing the quinazoline of compound 49, retained low nanomolar potency (IC 50 = 9.3 nM). 117 120 Easton Pharma discovered yogliptin 53 by replacing the quinazoline with 5-fluorobenzothiazole, which is a long-acting once-weekly DPP-4 inhibitor and currently in phase III clinical trials in China.…”

Section: Butynyl-based Analogues Of Linagliptinmentioning

confidence: 98%

“…117 Compound 50, with a 2-cyanobenzyl replacing the quinazoline of compound 49, retained low nanomolar potency (IC 50 = 9.3 nM). 117 120 Easton Pharma discovered yogliptin 53 by replacing the quinazoline with 5-fluorobenzothiazole, which is a long-acting once-weekly DPP-4 inhibitor and currently in phase III clinical trials in China. 121,122 Our group discovered some structurally novel DPP-4 inhibitors by focusing on the design of substituted benzoic acids and esters to interact with both Lys554 and Trp629 in the S 1 ′ and S 2 ′ pockets.…”

Section: Butynyl-based Analogues Of Linagliptinmentioning

confidence: 98%

“…Novartis identified the novel deazaxanthine 48 as a potent (IC 50 = 4.0 nM) and highly selective DPP-4 inhibitor . Merck discovered that tricyclic guanines can serve as isosteric substitutes for the xanthine scaffold . Compound 49 achieved subnanomolar potency (IC 50 = 0.4 nM) and demonstrated oral activity in vivo in the mouse glucose tolerance test .…”

Section: Structural Evolution From Lead Compounds To Long-acting Dpp-...mentioning

confidence: 99%

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Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants

Li,

Deng,

et al. 2023

J. Med. Chem.

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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.

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“…Pissarnitski et al designed and synthesized new purine scaffolds by isosteric replacement of xanthines with guanine scaffolds and evaluated them for DPP‐4 inhibition. All the synthesized compounds showed sub‐nanomolar potency range with compound 19 showing the highest in vitro activity (IC 50 = 0.42 nM).…”

Section: Dpp‐4 Inhibitors Actionmentioning

confidence: 99%

Emergence of promising novel DPP‐4 inhibitory heterocycles as anti‐diabetic agents: A review

Rohilla¹,

Gupta²,

Pathak³

et al. 2018

Archiv der Pharmazie

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Diabetes has turned out to be an epidemic in the recent years all over the world, and today it has become a burden on the healthcare system. Over the years, with technological advancements, different classes of antidiabetic medications have emerged, like sulfonylureas, biguanides, alpha-glucosidase inhibitors, and thiazolidinediones, but these are often loaded with serious aftermaths like hypoglycemia, weight gain, cardiovascular and renal issues. Dipeptidyl peptidase-4 (DPP-4) inhibition is an exciting and new approach in the treatment of type-2 diabetes. DPP-4 inhibitors or "gliptins" are weight neutral, pose lesser risk of hypoglycemia, and provide a long-term post-meal glycemic control. In this review, an attempt has been made to investigate novel potential compounds that can be added to the existing list of anti-diabetic drugs.

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Scaffold-hopping from xanthines to tricyclic guanines: A case study of dipeptidyl peptidase 4 (DPP4) inhibitors

Cited by 12 publications

References 35 publications

In Silico Approach for Screening of the Indonesian Medicinal Plants Database to Discover Potential Dipeptidyl Peptidase-4 Inhibitors

In Silico Approach for Screening of the Indonesian Medicinal Plants Database to Discover Potential Dipeptidyl Peptidase-4 Inhibitors

Development of Long-Acting Dipeptidyl Peptidase-4 Inhibitors: Structural Evolution and Long-Acting Determinants

Emergence of promising novel DPP‐4 inhibitory heterocycles as anti‐diabetic agents: A review

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