A comparative study of the binding properties, dipeptidyl peptidase-4 (DPP-4) inhibitory activity and glucose-lowering efficacy of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin in mice

Berger, Joel P.; SinhaRoy, Ranabir; Pocai, Alessandro; Kelly, Theresa M.; Scapin, Giovanna; Gao, Ying-Duo; Pryor, Kelly Ann D.; Wu, Joseph K.; Eiermann, George J.; Xu, Shiyao S.; Zhang, Xiaoping; Tatosian, Daniel A.; Weber, Ann E.; Thornberry, Nancy A.; Carr, Richard D.

doi:10.1002/edm2.2

Title: A comparative study of the binding properties, dipeptidyl peptidase-4 (DPP-4) inhibitory activity and glucose-lowering efficacy of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin in mice

Journal Article · Fri Nov 24 00:00:00 UTC 2017 · Endocrinology, diabetes & metabolism

DOI: https://doi.org/10.1002/edm2.2 · OSTI ID:1630018

Berger, Joel P. ^[1]; SinhaRoy, Ranabir ^[2]; Pocai, Alessandro ^[2]; Kelly, Theresa M. ^[2]; Scapin, Giovanna ^[2]; Gao, Ying-Duo ^[2]; Pryor, Kelly Ann D. ^[2]; Wu, Joseph K. ^[2]; Eiermann, George J. ^[2]; Xu, Shiyao S. ^[2]; Zhang, Xiaoping ^[2]; Tatosian, Daniel A. ^[2]; Weber, Ann E. ^[2]; Thornberry, Nancy A. ^[2];

^[3]

Merck& Co., Inc., Kenilworth, NJ (United States); DOE/OSTI
Merck& Co., Inc., Kenilworth, NJ (United States)
MSD A/S Copenhagen (Denmark); Univ. College London (United Kingdom)

Aims: Since 2006, DPP-4 inhibitors have become established therapy for the treatment of type 2 diabetes. Despite sharing a common mechanism of action, considerable chemical diversity exists amongst members of the DPP-4 inhibitor class, raising the question as to whether structural differences may result in differentiated enzyme inhibition and antihyperglycaemic activity. Methods: We have compared the binding properties of the most commonly used inhibitors and have investigated the relationship between their inhibitory potency at the level of the enzyme and their acute glucose-lowering efficacy. Results: Firstly, using a combination of published crystal structures and in-house data, we demonstrated that the binding site utilized by all of the DPP-4 inhibitors assessed was the same as that used by neuropeptide Y, supporting the hypothesis that DPP-4 inhibitors are able to competitively inhibit endogenous substrates for the enzyme. Secondly, we ascertained that the enzymatic cleft of DPP-4 is a relatively large cavity which displays conformational flexibility to accommodate structurally diverse inhibitor molecules. Finally, we found that for all inhibitors, irrespective of their chemical structure, the inhibition of plasma DPP-4 enzyme activity correlates directly with acute plasma glucose lowering in mice. Conclusion: The common binding site utilized by different DPP-4 inhibitors enables similar competitive inhibition of the cleavage of the endogenous DPP-4 substrates. Furthermore, despite chemical diversity and a range of binding potencies observed amongst the DPP-4 inhibitors, a direct relationship between enzyme inhibition in the plasma and glucose lowering is evident in mice for each member of the classes studied.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1630018

Journal Information:: Endocrinology, diabetes & metabolism, Journal Name: Endocrinology, diabetes & metabolism Journal Issue: 1 Vol. 1; ISSN 2398-9238

Publisher:: WileyCopyright Statement

Country of Publication:: United States

Language:: English

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Efficacy and Safety of Switching to Teneligliptin in Patients with Type 2 Diabetes Inadequately Controlled with Dipeptidyl Peptidase-4 Inhibitors: A 12-Week Interim Report Kim, Hae Jin; Kim, Young Sik; Lee, Chang Beom Diabetes Therapy, Vol. 10, Issue 4 https://doi.org/10.1007/s13300-019-0628-0	journal	May 2019
Saxagliptin but Not Sitagliptin Inhibits CaMKII and PKC via DPP9 Inhibition in Cardiomyocytes Koyani, Chintan N.; Trummer, Christopher; Shrestha, Niroj Frontiers in Physiology, Vol. 9 https://doi.org/10.3389/fphys.2018.01622	journal	November 2018
Solid-State Characterization of Different Crystalline Forms of Sitagliptin Stofella, Nayana C. F.; Veiga, Andressa; Oliveira, Laiane J. Materials, Vol. 12, Issue 15 https://doi.org/10.3390/ma12152351	journal	July 2019
Fragment-Based Drug Design to Discover Novel Inhibitor of Dipeptidyl Peptidase-4 (DPP-4) as a Potential Drug for Type 2 Diabetes Therapy Ningsih, Eka Gunarti; Hidayat, Muhammad Fauzi; Tambunan, Usman Sumo Friend Bioinformatics and Biomedical Engineering https://doi.org/10.1007/978-3-030-17938-0_2	book	January 2019
Efficacy and Safety of Switching to Teneligliptin in Patients with Type 2 Diabetes Inadequately Controlled with Dipeptidyl Peptidase-4 Inhibitors: A 12-Week Interim Report Kim, Hae Jin; Kim, Young Sik; Lee, Chang Beom Diabetes Therapy, Vol. 10, Issue 4 https://doi.org/10.1007/s13300-019-0628-0	journal	May 2019
DPP-4 Inhibitors: Renoprotective Potential and Pharmacokinetics in Type 2 Diabetes Mellitus Patients with Renal Impairment Mikov, Momir; Pavlović, Nebojša; Stanimirov, Bojan European Journal of Drug Metabolism and Pharmacokinetics, Vol. 45, Issue 1 https://doi.org/10.1007/s13318-019-00570-y	journal	August 2019
Comorbid diabetes results in immune dysregulation and enhanced disease severity following MERS-CoV infection Kulcsar, Kirsten A.; Coleman, Christopher M.; Beck, Sarah E. JCI Insight, Vol. 4, Issue 20 https://doi.org/10.1172/jci.insight.131774	journal	October 2019
Solid-State Characterization of Different Crystalline Forms of Sitagliptin Stofella, Nayana C. F.; Veiga, Andressa; Oliveira, Laiane J. Materials, Vol. 12, Issue 15 https://doi.org/10.3390/ma12152351	journal	July 2019

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60 APPLIED LIFE SCIENCES
alogliptin
dipeptidyl peptidase-4 inhibitor
linagliptin
saxagliptin
sitagliptin
type 2 diabetes
vildagliptin

Title: A comparative study of the binding properties, dipeptidyl peptidase-4 (DPP-4) inhibitory activity and glucose-lowering efficacy of the DPP-4 inhibitors alogliptin, linagliptin, saxagliptin, sitagliptin and vildagliptin in mice

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