Potency, selectivity and prolonged binding of saxagliptin to DPP4: maintenance of DPP4 inhibition by saxagliptin in vitro and ex vivo ... View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2012-04-04

AUTHORS

Aiying Wang, Charles Dorso, Lisa Kopcho, Gregory Locke, Robert Langish, Eric Harstad, Petia Shipkova, Jovita Marcinkeviciene, Lawrence Hamann, Mark S Kirby

ABSTRACT

BackgroundDipeptidylpeptidase 4 (DPP4) inhibitors have clinical benefit in patients with type 2 diabetes mellitus by increasing levels of glucose-lowering incretin hormones, such as glucagon-like peptide -1 (GLP-1), a peptide with a short half life that is secreted for approximately 1 hour following a meal. Since drugs with prolonged binding to their target have been shown to maximize pharmacodynamic effects while minimizing drug levels, we developed a time-dependent inhibitor that has a half-life for dissociation from DPP4 close to the duration of the first phase of GLP-1 release.ResultsSaxagliptin and its active metabolite (5-hydroxysaxagliptin) are potent inhibitors of human DPP4 with prolonged dissociation from its active site (Ki = 1.3 nM and 2.6 nM, t1/2 = 50 and 23 minutes respectively at 37°C). In comparison, both vildagliptin (3.5 minutes) and sitagliptin ( < 2 minutes) rapidly dissociated from DPP4 at 37°C. Saxagliptin and 5-hydroxysaxagliptin are selective for inhibition of DPP4 versus other DPP family members and a large panel of other proteases, and have similar potency and efficacy across multiple species.Inhibition of plasma DPP activity is used as a biomarker in animal models and clinical trials. However, most DPP4 inhibitors are competitive with substrate and rapidly dissociate from DPP4; therefore, the type of substrate, volume of addition and final concentration of substrate in these assays can change measured inhibition. We show that unlike a rapidly dissociating DPP4 inhibitor, inhibition of plasma DPP activity by saxagliptin and 5-hydroxysaxagliptin in an ex vivo assay was not dependent on substrate concentration when substrate was added rapidly because saxagliptin and 5-hydroxysaxagliptin dissociate slowly from DPP4, once bound. We also show that substrate concentration was important for rapidly dissociating DPP4 inhibitors.ConclusionsSaxagliptin and its active metabolite are potent, selective inhibitors of DPP4, with prolonged dissociation from its active site. They also demonstrate prolonged inhibition of plasma DPP4 ex vivo in animal models, which implies that saxagliptin and 5-hydroxysaxagliptin would continue to inhibit DPP4 during rapid increases in substrates in vivo. More... »

PAGES

2

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/1471-2210-12-2

DOI

http://dx.doi.org/10.1186/1471-2210-12-2

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1003409735

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/22475049


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35 schema:description BackgroundDipeptidylpeptidase 4 (DPP4) inhibitors have clinical benefit in patients with type 2 diabetes mellitus by increasing levels of glucose-lowering incretin hormones, such as glucagon-like peptide -1 (GLP-1), a peptide with a short half life that is secreted for approximately 1 hour following a meal. Since drugs with prolonged binding to their target have been shown to maximize pharmacodynamic effects while minimizing drug levels, we developed a time-dependent inhibitor that has a half-life for dissociation from DPP4 close to the duration of the first phase of GLP-1 release.ResultsSaxagliptin and its active metabolite (5-hydroxysaxagliptin) are potent inhibitors of human DPP4 with prolonged dissociation from its active site (Ki = 1.3 nM and 2.6 nM, t1/2 = 50 and 23 minutes respectively at 37°C). In comparison, both vildagliptin (3.5 minutes) and sitagliptin ( < 2 minutes) rapidly dissociated from DPP4 at 37°C. Saxagliptin and 5-hydroxysaxagliptin are selective for inhibition of DPP4 versus other DPP family members and a large panel of other proteases, and have similar potency and efficacy across multiple species.Inhibition of plasma DPP activity is used as a biomarker in animal models and clinical trials. However, most DPP4 inhibitors are competitive with substrate and rapidly dissociate from DPP4; therefore, the type of substrate, volume of addition and final concentration of substrate in these assays can change measured inhibition. We show that unlike a rapidly dissociating DPP4 inhibitor, inhibition of plasma DPP activity by saxagliptin and 5-hydroxysaxagliptin in an ex vivo assay was not dependent on substrate concentration when substrate was added rapidly because saxagliptin and 5-hydroxysaxagliptin dissociate slowly from DPP4, once bound. We also show that substrate concentration was important for rapidly dissociating DPP4 inhibitors.ConclusionsSaxagliptin and its active metabolite are potent, selective inhibitors of DPP4, with prolonged dissociation from its active site. They also demonstrate prolonged inhibition of plasma DPP4 ex vivo in animal models, which implies that saxagliptin and 5-hydroxysaxagliptin would continue to inhibit DPP4 during rapid increases in substrates in vivo.
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41 schema:keywords DPP activity
42 DPP family members
43 DPP4
44 DPP4 inhibition
45 DPP4 inhibitors
46 GLP-1 release
47 active metabolite
48 active site
49 activity
50 addition
51 animal models
52 assays
53 benefits
54 binding
55 biomarkers
56 clinical benefit
57 clinical trials
58 comparison
59 concentration
60 diabetes mellitus
61 dissociates
62 dissociation
63 drug levels
64 drugs
65 duration
66 effect
67 efficacy
68 ex vivo
69 family members
70 final concentration
71 first phase
72 glucagon-like peptide-1
73 half life
74 hormone
75 hours
76 human DPP4
77 increase
78 incretin hormones
79 inhibition
80 inhibition of DPP4
81 inhibitors
82 large panel
83 levels
84 life
85 maintenance
86 meal
87 measured inhibition
88 mellitus
89 members
90 metabolites
91 model
92 multiple species
93 panel
94 patients
95 peptide-1
96 peptides
97 pharmacodynamic effects
98 phase
99 plasma DPP4
100 potency
101 potent inhibitor
102 prolonged dissociation
103 prolonged inhibition
104 protease
105 rapid increase
106 release
107 saxagliptin
108 selective inhibitor
109 selectivity
110 short half life
111 similar potency
112 sitagliptin
113 sites
114 species
115 substrate
116 substrate concentration
117 target
118 time-dependent inhibitor
119 trials
120 type 2 diabetes mellitus
121 type of substrate
122 types
123 vildagliptin
124 vitro
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