|
Inhibition of human DPP4 in Caco-2 cells by fluorescene assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes.
Year : 2007
Volume : 50
Issue : 26
First Page : 6450
Last Page : 6453
Authors : Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, Pfrengle W, Guth B, Lotz R, Sieger P, Fuchs H, Himmelsbach F.
Abstract : A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
|
Inhibition of human hERG current at 1 uM
|
Homo sapiens
|
97.0
%
|
|
Journal : J. Med. Chem.
Title : 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes.
Year : 2007
Volume : 50
Issue : 26
First Page : 6450
Last Page : 6453
Authors : Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, Pfrengle W, Guth B, Lotz R, Sieger P, Fuchs H, Himmelsbach F.
Abstract : A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
|
Displacement of [N-methyl-3H]scopolamine from human recombinant muscarinic M1 receptor expressed in CHO cells
|
Homo sapiens
|
295.0
nM
|
|
Journal : J. Med. Chem.
Title : 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes.
Year : 2007
Volume : 50
Issue : 26
First Page : 6450
Last Page : 6453
Authors : Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, Pfrengle W, Guth B, Lotz R, Sieger P, Fuchs H, Himmelsbach F.
Abstract : A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
|
Inhibition of plasma DPP4 activity in Han Wistar rat at 1 mg/kg, po after 7 hrs
|
Rattus norvegicus
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes.
Year : 2007
Volume : 50
Issue : 26
First Page : 6450
Last Page : 6453
Authors : Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, Pfrengle W, Guth B, Lotz R, Sieger P, Fuchs H, Himmelsbach F.
Abstract : A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
|
Inhibition of plasma DPP4 activity in Beagle dog at 1 mg/kg, po after 7 hrs
|
Canis lupus familiaris
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes.
Year : 2007
Volume : 50
Issue : 26
First Page : 6450
Last Page : 6453
Authors : Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, Pfrengle W, Guth B, Lotz R, Sieger P, Fuchs H, Himmelsbach F.
Abstract : A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
|
Inhibition of plasma DPP4 activity in rhesus monkey at 1 mg/kg, po after 7 hrs
|
Macaca mulatta
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes.
Year : 2007
Volume : 50
Issue : 26
First Page : 6450
Last Page : 6453
Authors : Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, Pfrengle W, Guth B, Lotz R, Sieger P, Fuchs H, Himmelsbach F.
Abstract : A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
|
Reduction in plasma glucose excursion in db/db C57BL/KSJ mouse at 0.1 mg/kg, po by oral glucose tolerance test
|
Mus musculus
|
15.0
%
|
|
Journal : J. Med. Chem.
Title : 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes.
Year : 2007
Volume : 50
Issue : 26
First Page : 6450
Last Page : 6453
Authors : Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, Pfrengle W, Guth B, Lotz R, Sieger P, Fuchs H, Himmelsbach F.
Abstract : A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
|
Reduction in plasma glucose excursion in db/db C57BL/KSJ mouse at 1 mg/kg, po by oral glucose tolerance test
|
Mus musculus
|
66.0
%
|
|
Journal : J. Med. Chem.
Title : 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes.
Year : 2007
Volume : 50
Issue : 26
First Page : 6450
Last Page : 6453
Authors : Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, Pfrengle W, Guth B, Lotz R, Sieger P, Fuchs H, Himmelsbach F.
Abstract : A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
|
Inhibition of plasma DPP4 activity in db/db C57BL/KSJ mouse at 1 mg/kg, po after 30 mins of glucose administration
|
Mus musculus
|
76.0
%
|
|
Journal : J. Med. Chem.
Title : 8-(3-(R)-aminopiperidin-1-yl)-7-but-2-ynyl-3-methyl-1-(4-methyl-quinazolin-2-ylmethyl)-3,7-dihydropurine-2,6-dione (BI 1356), a highly potent, selective, long-acting, and orally bioavailable DPP-4 inhibitor for the treatment of type 2 diabetes.
Year : 2007
Volume : 50
Issue : 26
First Page : 6450
Last Page : 6453
Authors : Eckhardt M, Langkopf E, Mark M, Tadayyon M, Thomas L, Nar H, Pfrengle W, Guth B, Lotz R, Sieger P, Fuchs H, Himmelsbach F.
Abstract : A new chemical class of potent DPP-4 inhibitors structurally derived from the xanthine scaffold for the treatment of type 2 diabetes has been discovered and evaluated. Systematic structural variations have led to 1 (BI 1356), a highly potent, selective, long-acting, and orally active DPP-4 inhibitor that shows considerable blood glucose lowering in different animal species. 1 is currently undergoing clinical phase IIb trials and holds the potential for once-daily treatment of type 2 diabetics.
|
Inhibition of DPP4 in human Caco-2 cells after 1 hr
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 3,5-Dihydro-imidazo[4,5-d]pyridazin-4-ones: a class of potent DPP-4 inhibitors.
Year : 2008
Volume : 18
Issue : 11
First Page : 3158
Last Page : 3162
Authors : Eckhardt M, Hauel N, Himmelsbach F, Langkopf E, Nar H, Mark M, Tadayyon M, Thomas L, Guth B, Lotz R.
Abstract : Systematic variations of the xanthine scaffold in close analogs of development compound BI 1356 led to the class of 3,5-dihydro-imidazo[4,5-d]pyridazin-4-ones which provided, after substituent screening, a series of highly potent DPP-4 inhibitors.
|
Inhibition of human C-terminal step-tagged DPP4 expressed using baculovirus system
|
Homo sapiens
|
0.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel heterocyclic DPP-4 inhibitors for the treatment of type 2 diabetes.
Year : 2012
Volume : 22
Issue : 3
First Page : 1464
Last Page : 1468
Authors : Sutton JM, Clark DE, Dunsdon SJ, Fenton G, Fillmore A, Harris NV, Higgs C, Hurley CA, Krintel SL, MacKenzie RE, Duttaroy A, Gangl E, Maniara W, Sedrani R, Namoto K, Ostermann N, Gerhartz B, Sirockin F, Trappe J, Hassiepen U, Baeschlin DK.
Abstract : Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man.
|
Inhibition of M1 receptor
|
None
|
295.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel heterocyclic DPP-4 inhibitors for the treatment of type 2 diabetes.
Year : 2012
Volume : 22
Issue : 3
First Page : 1464
Last Page : 1468
Authors : Sutton JM, Clark DE, Dunsdon SJ, Fenton G, Fillmore A, Harris NV, Higgs C, Hurley CA, Krintel SL, MacKenzie RE, Duttaroy A, Gangl E, Maniara W, Sedrani R, Namoto K, Ostermann N, Gerhartz B, Sirockin F, Trappe J, Hassiepen U, Baeschlin DK.
Abstract : Novel deazaxanthine-based DPP-4 inhibitors have been identified that are potent (IC(50) <10nM) and highly selective versus other dipeptidyl peptidases. Their synthesis and SAR are reported, along with initial efforts to improve the PK profile through decoration of the deazaxanthine core. Optimisation of compound 3a resulted in the identification of compound (S)-4i, which displayed an improved in vitro and ADME profile. Further enhancements to the PK profile were possible by changing from the deazahypoxanthine to the deazaxanthine template, culminating in compound 12g, which displayed good ex vivo DPP-4 inhibition and a superior PK profile in rat, suggestive of once daily dosing in man.
|
Inhibition of DPP4 in human plasma using Gly-Pro-AMC as substrate by fluorimetric analysis
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors.
Year : 2012
Volume : 20
Issue : 19
First Page : 5864
Last Page : 5883
Authors : Ikuma Y, Hochigai H, Kimura H, Nunami N, Kobayashi T, Uchiyama K, Furuta Y, Sakai M, Horiguchi M, Masui Y, Okazaki K, Sato Y, Nakahira H.
Abstract : In recent years, dipeptidyl peptidase IV inhibitors have been noted as valuable agents for treatment of type 2 diabetes. Herein, we report the discovery of a novel potent DPP-4 inhibitor with 3H-imidazo[4,5-c]quinolin-4(5H)-one as skeleton. After efficient optimization of the lead compound 2a at the 7- and 8-positions using a docking study, we found 28 as a novel DPP-4 inhibitor with excellent selectivity against various DPP-4 homologues. Compound 28 showed strong DPP-4 inhibitory activity compared to marketed DPP-4 inhibitors. We also found that a carboxyl group at the 7-position could interact with the residue of Lys554 to form a salt bridge. Additionally, introduction of a carboxyl group to 7-position led to both activity enhancement and reduced risk for hERG channel inhibition and induced phospholipidosis. In our synthesis of compounds with 7-carboxyl group, we achieved efficient regioselective synthesis using bulky ester in the intramolecular palladium coupling reaction.
|
Inhibition of FAPalpha
|
None
|
89.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Discovery of 3H-imidazo[4,5-c]quinolin-4(5H)-ones as potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors.
Year : 2012
Volume : 20
Issue : 19
First Page : 5864
Last Page : 5883
Authors : Ikuma Y, Hochigai H, Kimura H, Nunami N, Kobayashi T, Uchiyama K, Furuta Y, Sakai M, Horiguchi M, Masui Y, Okazaki K, Sato Y, Nakahira H.
Abstract : In recent years, dipeptidyl peptidase IV inhibitors have been noted as valuable agents for treatment of type 2 diabetes. Herein, we report the discovery of a novel potent DPP-4 inhibitor with 3H-imidazo[4,5-c]quinolin-4(5H)-one as skeleton. After efficient optimization of the lead compound 2a at the 7- and 8-positions using a docking study, we found 28 as a novel DPP-4 inhibitor with excellent selectivity against various DPP-4 homologues. Compound 28 showed strong DPP-4 inhibitory activity compared to marketed DPP-4 inhibitors. We also found that a carboxyl group at the 7-position could interact with the residue of Lys554 to form a salt bridge. Additionally, introduction of a carboxyl group to 7-position led to both activity enhancement and reduced risk for hERG channel inhibition and induced phospholipidosis. In our synthesis of compounds with 7-carboxyl group, we achieved efficient regioselective synthesis using bulky ester in the intramolecular palladium coupling reaction.
|
Inhibition of dipeptidyl peptidase 4 (unknown origin)
|
Homo sapiens
|
1.0
nM
|
|
Journal : Med Chem Res
Title : Computational studies on structurally diverse dipeptidyl peptidase IV inhibitors: an approach for new antidiabetic drug development
Year : 2013
Volume : 22
Issue : 9
First Page : 4505
Last Page : 4521
Authors : Patel B, Ghate M
|
Inhibition of DPP4 in human seminal plasma using Gly-Pro-p-nitroanilide as substrate incubated for 15 mins prior to substrate addition
|
Homo sapiens
|
2.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold.
Year : 2013
Volume : 4
Issue : 5
First Page : 491
Last Page : 496
Authors : Jansen K, Heirbaut L, Cheng JD, Joossens J, Ryabtsova O, Cos P, Maes L, Lambeir AM, De Meester I, Augustyns K, Van der Veken P.
Abstract : Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp(2) hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10(3)) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.
|
Inhibition of mouse recombinant FAP expressed in HEK293 cells using Ala-Pro-p-nitroanilide as substrate incubated for 15 mins prior to substrate addition
|
Mus musculus
|
370.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Selective Inhibitors of Fibroblast Activation Protein (FAP) with a (4-Quinolinoyl)-glycyl-2-cyanopyrrolidine Scaffold.
Year : 2013
Volume : 4
Issue : 5
First Page : 491
Last Page : 496
Authors : Jansen K, Heirbaut L, Cheng JD, Joossens J, Ryabtsova O, Cos P, Maes L, Lambeir AM, De Meester I, Augustyns K, Van der Veken P.
Abstract : Fibroblast activation protein (FAP) is a serine protease that is generally accepted to play an important role in tumor growth and other diseases involving tissue remodeling. Currently there are no FAP inhibitors with reported selectivity toward both the closely related dipeptidyl peptidases (DPPs) and prolyl oligopeptidase (PREP). We present the discovery of a new class of FAP inhibitors with a N-(4-quinolinoyl)-Gly-(2-cyanopyrrolidine) scaffold. We have explored the effects of substituting the quinoline ring and varying the position of its sp(2) hybridized nitrogen atom. The most promising inhibitors combined low nanomolar FAP inhibition and high selectivity indices (>10(3)) with respect to both the DPPs and PREP. Preliminary experiments on a representative inhibitor demonstrate that plasma stability, kinetic solubility, and log D of this class of compounds can be expected to be satisfactory.
|
Inhibition of DPP4 in human Caco2 cells using H-Ala-Pro-7-amido-4-trifluoromethylcoumarin as substrate after 1 hr by fluorescence assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthetic approaches to the 2011 new drugs.
Year : 2013
Volume : 21
Issue : 11
First Page : 2795
Last Page : 2825
Authors : Ding HX, Liu KK, Sakya SM, Flick AC, O'Donnell CJ.
Abstract : New drugs are introduced to the market every year and each represents a privileged structure for its biological target. These new chemical entities (NCEs) provide insights into molecular recognition and also serve as leads for designing future new drugs. This review covers the synthesis of 26 NCEs that were launched in the world in 2011.
|
Inhibition of plasma DPP4 (unknown origin) after 24 hrs
|
Homo sapiens
|
70.0
%
|
|
Journal : J. Med. Chem.
Title : Dipeptidyl peptidase IV and its inhibitors: therapeutics for type 2 diabetes and what else?
Year : 2014
Volume : 57
Issue : 6
First Page : 2197
Last Page : 2212
Authors : Juillerat-Jeanneret L.
Abstract : The proline-specific dipeptidyl aminopeptidase IV (DPP IV, DPP-4, CD26), widely expressed in mammalians, releases X-Pro/Ala dipeptides from the N-terminus of peptides. DPP IV is responsible of the degradation of the incretin peptide hormones regulating blood glucose levels. Several families of DPP IV inhibitors have been synthesized and evaluated. Their positive effects on the degradation of the incretins and the control of blood glucose levels have been demonstrated in biological models and in clinical trials. Presently, several DPP IV inhibitors, the "gliptins", are approved for type 2 diabetes or are under clinical evaluation. However, the gliptins may also be of therapeutic interest for other diseases beyond the inhibition of incretin degradation. In this Perspective, the biological functions and potential substrates of DPP IV enzymes are reviewed and the characteristics of the DPP IV inhibitors are discussed in view of type 2 diabetes and further therapeutic interest.
|
Inhibition of recombinant mouse FAP purified from HEK293 cell supernatant using Ala-Pro-p-nitroanilide as substrate by spectrophotometry
|
Mus musculus
|
370.0
nM
|
|
Journal : J. Med. Chem.
Title : Extended structure-activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP).
Year : 2014
Volume : 57
Issue : 7
First Page : 3053
Last Page : 3074
Authors : Jansen K, Heirbaut L, Verkerk R, Cheng JD, Joossens J, Cos P, Maes L, Lambeir AM, De Meester I, Augustyns K, Van der Veken P.
Abstract : Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncology applications. We previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, we explore in detail the structure-activity relationship around this core scaffold. We report extensively optimized compounds that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo.
|
Inhibition of DPP4 purified from human seminal plasma using Gly-Pro-p-nitroanilide as substrate by spectrophotometry
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Extended structure-activity relationship and pharmacokinetic investigation of (4-quinolinoyl)glycyl-2-cyanopyrrolidine inhibitors of fibroblast activation protein (FAP).
Year : 2014
Volume : 57
Issue : 7
First Page : 3053
Last Page : 3074
Authors : Jansen K, Heirbaut L, Verkerk R, Cheng JD, Joossens J, Cos P, Maes L, Lambeir AM, De Meester I, Augustyns K, Van der Veken P.
Abstract : Fibroblast activation protein (FAP) is a serine protease related to dipeptidyl peptidase IV (DPPIV). It has been convincingly linked to multiple disease states involving remodeling of the extracellular matrix. FAP inhibition is investigated as a therapeutic option for several of these diseases, with most attention so far devoted to oncology applications. We previously discovered the N-4-quinolinoyl-Gly-(2S)-cyanoPro scaffold as a possible entry to highly potent and selective FAP inhibitors. In the present study, we explore in detail the structure-activity relationship around this core scaffold. We report extensively optimized compounds that display low nanomolar inhibitory potency and high selectivity against the related dipeptidyl peptidases (DPPs) DPPIV, DPP9, DPPII, and prolyl oligopeptidase (PREP). The log D values, plasma stabilities, and microsomal stabilities of selected compounds were found to be highly satisfactory. Pharmacokinetic evaluation in mice of selected inhibitors demonstrated high oral bioavailability, plasma half-life, and the potential to selectively and completely inhibit FAP in vivo.
|
Inhibition of human BCRP expressed in MDCK2 cells assessed as reduction of [3H]E-sul substrate transport up to 100 uM by liquid scintillation counting
|
Homo sapiens
|
24.7
%
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.
Year : 2013
Volume : 41
Issue : 1
First Page : 149
Last Page : 158
Authors : Ishiguro N, Shimizu H, Kishimoto W, Ebner T, Schaefer O.
Abstract : Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.
|
Inhibition of OAT1 (unknown origin) expressed in HEK293 cells assessed as reduction of [3H]PAH substrate uptake at 100 uM by liquid scintillation counting
|
Homo sapiens
|
1.07
%
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.
Year : 2013
Volume : 41
Issue : 1
First Page : 149
Last Page : 158
Authors : Ishiguro N, Shimizu H, Kishimoto W, Ebner T, Schaefer O.
Abstract : Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.
|
Inhibition of OAT3 (unknown origin) expressed in HEK293 cells assessed as reduction of [3H]E-sul substrate uptake at 100 uM by liquid scintillation counting
|
Homo sapiens
|
0.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.
Year : 2013
Volume : 41
Issue : 1
First Page : 149
Last Page : 158
Authors : Ishiguro N, Shimizu H, Kishimoto W, Ebner T, Schaefer O.
Abstract : Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.
|
Inhibition of OAT4 (unknown origin) expressed in HEK293 cells assessed as reduction of [3H]E-sul substrate uptake at 100 uM by liquid scintillation counting
|
Homo sapiens
|
0.0
%
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.
Year : 2013
Volume : 41
Issue : 1
First Page : 149
Last Page : 158
Authors : Ishiguro N, Shimizu H, Kishimoto W, Ebner T, Schaefer O.
Abstract : Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.
|
Inhibition of OATP1B1 (unknown origin) expressed in HEK293 cells assessed as reduction of [3H]E217betaG substrate uptake at 100 uM by liquid scintillation counting
|
Homo sapiens
|
35.5
%
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.
Year : 2013
Volume : 41
Issue : 1
First Page : 149
Last Page : 158
Authors : Ishiguro N, Shimizu H, Kishimoto W, Ebner T, Schaefer O.
Abstract : Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.
|
Inhibition of OATP1B3 (unknown origin) expressed in HEK293 cells assessed as reduction of [3H]CCK8 substrate uptake at 100 uM by liquid scintillation counting
|
Homo sapiens
|
3.39
%
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.
Year : 2013
Volume : 41
Issue : 1
First Page : 149
Last Page : 158
Authors : Ishiguro N, Shimizu H, Kishimoto W, Ebner T, Schaefer O.
Abstract : Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.
|
Inhibition of OCTN1 (unknown origin) expressed in HEK293 cells assessed as reduction of [3H]ergothioneine substrate uptake at 100 uM by liquid scintillation counting
|
Homo sapiens
|
19.4
%
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.
Year : 2013
Volume : 41
Issue : 1
First Page : 149
Last Page : 158
Authors : Ishiguro N, Shimizu H, Kishimoto W, Ebner T, Schaefer O.
Abstract : Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.
|
Inhibition of OCTN2 (unknown origin) expressed in HEK293 cells assessed as reduction of [3H]carnitine substrate uptake at 100 uM by liquid scintillation counting
|
Homo sapiens
|
15.5
%
|
|
Journal : Drug Metab. Dispos.
Title : Evaluation and prediction of potential drug-drug interactions of linagliptin using in vitro cell culture methods.
Year : 2013
Volume : 41
Issue : 1
First Page : 149
Last Page : 158
Authors : Ishiguro N, Shimizu H, Kishimoto W, Ebner T, Schaefer O.
Abstract : Linagliptin is a highly potent dipeptidyl peptidase-4 (DPP-4) inhibitor approved for the treatment of type 2 diabetes. Unlike other DPP-4 inhibitors, linagliptin is cleared primarily via the bile and gut. We used a panel of stably and transiently transfected cell lines to elucidate the carrier-mediated transport processes that are involved in linagliptin disposition in vivo and to assess the potential for drug-drug interactions (DDIs). Our results demonstrate that linagliptin is a substrate of organic cation transporter 2 (OCT2) and P-glycoprotein (P-gp) but not of organic anion-transporting polypeptide 1B1 and 1B3; organic anion transporter 1, 3, and 4; OCT1; or organic cation/carnitine transporter 1 and 2, suggesting that OCT2 and P-gp play a role in the disposition of linagliptin in vivo. Linagliptin inhibits transcellular transport of digoxin by P-gp with an apparent IC(50) of 66.1 μM, but it did not inhibit activity of multidrug resistance-associated protein 2 and breast cancer resistance protein as represented by transport of probe substrate into membrane vesicles from respective transporter-expressing cells. In addition, the inhibitory effect of linagliptin on major solute carrier transporter isoforms was investigated. Linagliptin showed inhibitory potency against only OCT1 and OCT2 out of all major solute carrier transporter isoforms examined, and those inhibition potencies, evaluated using three different in vitro probe substrates, were substrate-specific. Considering the low therapeutic plasma concentration of linagliptin, our data clearly suggest a very low risk for transporter-mediated DDIs with comedications in clinical practice.
|
Binding affinity to FAP (unknown origin)
|
Homo sapiens
|
370.0
nM
|
|
Journal : MedChemComm
Title : Selective inhibitors of fibroblast activation protein (FAP) with a xanthine scaffold
Year : 2014
Volume : 5
Issue : 11
First Page : 1700
Last Page : 1707
Authors : Jansen K, De Winter H, Heirbaut L, Cheng JD, Joossens J, Lambeir A, De Meester I, Augustyns K, Van der Veken P
|
Binding affinity to DPP4 (unknown origin)
|
Homo sapiens
|
2.0
nM
|
|
Journal : MedChemComm
Title : Selective inhibitors of fibroblast activation protein (FAP) with a xanthine scaffold
Year : 2014
Volume : 5
Issue : 11
First Page : 1700
Last Page : 1707
Authors : Jansen K, De Winter H, Heirbaut L, Cheng JD, Joossens J, Lambeir A, De Meester I, Augustyns K, Van der Veken P
|
Inhibition of FAP (unknown origin)
|
Homo sapiens
|
89.0
nM
|
|
Journal : MedChemComm
Title : Selective inhibitors of fibroblast activation protein (FAP) with a xanthine scaffold
Year : 2014
Volume : 5
Issue : 11
First Page : 1700
Last Page : 1707
Authors : Jansen K, De Winter H, Heirbaut L, Cheng JD, Joossens J, Lambeir A, De Meester I, Augustyns K, Van der Veken P
|
Inhibition of human DPP4
|
Homo sapiens
|
1.0
nM
|
|
Journal : MedChemComm
Title : Selective inhibitors of fibroblast activation protein (FAP) with a xanthine scaffold
Year : 2014
Volume : 5
Issue : 11
First Page : 1700
Last Page : 1707
Authors : Jansen K, De Winter H, Heirbaut L, Cheng JD, Joossens J, Lambeir A, De Meester I, Augustyns K, Van der Veken P
|
Inhibition of human DPP4 preincubated for 30 mins followed by Gly-Pro-AMC addition measured for 50 mins by continuous fluorescence assay
|
Homo sapiens
|
0.1
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes.
Year : 2016
Volume : 7
Issue : 5
First Page : 498
Last Page : 501
Authors : Wu WL, Hao J, Domalski M, Burnett DA, Pissarnitski D, Zhao Z, Stamford A, Scapin G, Gao YD, Soriano A, Kelly TM, Yao Z, Powles MA, Chen S, Mei H, Hwa J.
Abstract : In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.
|
Inhibition of FAP (unknown origin) preincubated for 20 mins followed by Nle-Pro-AMC addition measured for 40 mins by continuous fluorescence assay
|
Homo sapiens
|
70.8
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes.
Year : 2016
Volume : 7
Issue : 5
First Page : 498
Last Page : 501
Authors : Wu WL, Hao J, Domalski M, Burnett DA, Pissarnitski D, Zhao Z, Stamford A, Scapin G, Gao YD, Soriano A, Kelly TM, Yao Z, Powles MA, Chen S, Mei H, Hwa J.
Abstract : In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.
|
DPP-IV Activity InhibitoryAssay: Gly-Pro-7-amido-4-methylcoumarin can be hydrolyzed by dipeptidyl peptidase IV (DPP-IV) at room temperature, to generate 7-amido-4-methyl coumarin, which can emit fluorescence with wavelength of 460 nm at excitation wavelength of 355 nm. The variation of the product amount can be determined by the variation of fluorescence intensity, so as to reflect the activity level of the enzyme. The dipeptidyl peptidase IV (DPP-IV), DPP-IV buffer and test samples were used to construct the reaction system of 200 uL, while the blank control (without enzyme and samples) and negative control (without samples) having the same volume were set up. The reaction system and the controls were reacted at room temperature for 10 min, and then dipeptidyl peptidase IV substrate was added thereto respectively, then reacted at room temperature for 30 min. The fluorescence intensity F (excitation wavelength of 355 nm, emission wavelength of 460 nm) was determined.
|
Homo sapiens
|
1.0
nM
|
|
Title : Xanthine derivative
Year : 2016
|
DPP-IV Assay: 50 μl substrate solution (AFC; AFC is amido-4-trifluoromethylcoumarin), final concentration 100 μM, were placed in black microtitre plates. 20 μl of assay buffer (final concentrations 50 mM Tris HCl pH 7.8, 50 mM NaCl, 1% DMSO) was pipetted in. The reaction was started by adding 30 μl of solubilised Caco-2 protein (final concentration 0.14 μg of protein per well). The test substances to be investigated were typically added prediluted in 20 μl, and the volume of assay buffer was then reduced accordingly. The reaction was carried out at ambient temperature, incubating for 60 minutes. Then the fluorescence was measured in a Victor 1420 Multilabel Counter, the excitation wavelength being 405 nm and the emission wavelength being 535 nm. Blank readings (corresponding to 0% activity) were obtained in mixtures without any Caco-2 protein (volume replaced by assay buffer), control values (corresponding to 100% activity) were obtained in mixtures with no substance added.
|
Homo sapiens
|
1.0
nM
|
|
Title : 8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
Year : 2016
|
Inhibition of Porphyromonas gingivalis N-terminal His-tagged DPP4 expressed in Escherichia coli at 10 uM using Gly-Pro-p-nitroanilide as substrate relative to control
|
Porphyromonas gingivalis
|
50.0
%
|
|
Journal : Eur J Med Chem
Title : Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling.
Year : 2017
Volume : 139
First Page : 482
Last Page : 491
Authors : Rea D, Van Elzen R, De Winter H, Van Goethem S, Landuyt B, Luyten W, Schoofs L, Van Der Veken P, Augustyns K, De Meester I, Fülöp V, Lambeir AM.
Abstract : The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P. gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biofilm formation and were more infective. The X-ray crystal structure of P. gingivalis DPP4 was solved at 2.2 Å resolution. Despite a sequence identity of 32%, the overall structure of the dimer was conserved between P. gingivalis DPP4 and mammalian orthologues. The structures of the substrate binding sites were also conserved, except for the region called S2-extensive, which is exploited by specific human DPP4 inhibitors currently used as antidiabetic drugs. Screening of a collection of 450 compounds as inhibitors revealed a structure-activity relationship that mimics in part that of mammalian DPP9. The functional similarity between human and bacterial DPP4 was confirmed using 124 potential peptide substrates.
|
Inhibition of Porphyromonas gingivalis N-terminal His-tagged DPP4 expressed in Escherichia coli at 100 uM using Gly-Pro-p-nitroanilide as substrate relative to control
|
Porphyromonas gingivalis
|
50.0
%
|
|
Journal : Eur J Med Chem
Title : Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling.
Year : 2017
Volume : 139
First Page : 482
Last Page : 491
Authors : Rea D, Van Elzen R, De Winter H, Van Goethem S, Landuyt B, Luyten W, Schoofs L, Van Der Veken P, Augustyns K, De Meester I, Fülöp V, Lambeir AM.
Abstract : The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P. gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biofilm formation and were more infective. The X-ray crystal structure of P. gingivalis DPP4 was solved at 2.2 Å resolution. Despite a sequence identity of 32%, the overall structure of the dimer was conserved between P. gingivalis DPP4 and mammalian orthologues. The structures of the substrate binding sites were also conserved, except for the region called S2-extensive, which is exploited by specific human DPP4 inhibitors currently used as antidiabetic drugs. Screening of a collection of 450 compounds as inhibitors revealed a structure-activity relationship that mimics in part that of mammalian DPP9. The functional similarity between human and bacterial DPP4 was confirmed using 124 potential peptide substrates.
|
Inhibition of human DPP4
|
Homo sapiens
|
2.0
nM
|
|
Journal : Eur J Med Chem
Title : Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling.
Year : 2017
Volume : 139
First Page : 482
Last Page : 491
Authors : Rea D, Van Elzen R, De Winter H, Van Goethem S, Landuyt B, Luyten W, Schoofs L, Van Der Veken P, Augustyns K, De Meester I, Fülöp V, Lambeir AM.
Abstract : The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P. gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biofilm formation and were more infective. The X-ray crystal structure of P. gingivalis DPP4 was solved at 2.2 Å resolution. Despite a sequence identity of 32%, the overall structure of the dimer was conserved between P. gingivalis DPP4 and mammalian orthologues. The structures of the substrate binding sites were also conserved, except for the region called S2-extensive, which is exploited by specific human DPP4 inhibitors currently used as antidiabetic drugs. Screening of a collection of 450 compounds as inhibitors revealed a structure-activity relationship that mimics in part that of mammalian DPP9. The functional similarity between human and bacterial DPP4 was confirmed using 124 potential peptide substrates.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
1.59
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of human DPP4 in pH 7.4 Tris buffer using AP-7-ATFMC as substrate preincubated for 15 mins followed by substrate addition by microplate reader analysis relative to control
|
Homo sapiens
|
96.24
%
|
|
Journal : Eur J Med Chem
Title : Synthesis and discovery of triazolo-pyridazine-6-yl-substituted piperazines as effective anti-diabetic drugs; evaluated over dipeptidyl peptidase-4 inhibition mechanism and insulinotropic activities.
Year : 2020
Volume : 187
First Page : 111912
Last Page : 111912
Authors : Bindu B, Vijayalakshmi S, Manikandan A.
Abstract : A family of 12 triazolo-pyridazine-6-yl-substituted piperazines (5a-l) was synthesized and evaluated for their Dipeptidyl peptidase-4 (DPP-4) inhibition potentials in order to develop them as anti-diabetic medications. In the two-step synthesis process, 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine was synthesized with one-pot mode using pyridine, 3,6-dichloropyridazine 5-(3-methyl-phenyl)tetrazole in toluene. Conjugating corresponding 2° amines with 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine afforded the target triazolo-pyridazine-6-yl-substituted piperazines (5a-l). DPP-4 inhibition potential of these compounds was testified in silico and in nitro along with their insulinotropic activities in 832/13 INS-1 cells. H2O2 radical scavenging assay and MTT assay were conducted to assess the antioxidant and cytotoxicity of these compounds respectively. Molecular docking and ELISA based enzyme inhibition assay results revealed the strong inhibition potential of the target compounds. MTT assay results indicated a maximum dose of 2.5 nM (IC50 1.25 nM) could be used and above this level vital for the cells. Compounds 5a, 5c, 5g and 5i were found with excellent antioxidant and insulinotropic activity up to 99%.
|
Inhibition of human DPP4 in pH 7.4 Tris buffer using AP-7-ATFMC as substrate preincubated for 15 mins followed by substrate addition by microplate reader analysis
|
Homo sapiens
|
1.25
nM
|
|
Journal : Eur J Med Chem
Title : Synthesis and discovery of triazolo-pyridazine-6-yl-substituted piperazines as effective anti-diabetic drugs; evaluated over dipeptidyl peptidase-4 inhibition mechanism and insulinotropic activities.
Year : 2020
Volume : 187
First Page : 111912
Last Page : 111912
Authors : Bindu B, Vijayalakshmi S, Manikandan A.
Abstract : A family of 12 triazolo-pyridazine-6-yl-substituted piperazines (5a-l) was synthesized and evaluated for their Dipeptidyl peptidase-4 (DPP-4) inhibition potentials in order to develop them as anti-diabetic medications. In the two-step synthesis process, 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine was synthesized with one-pot mode using pyridine, 3,6-dichloropyridazine 5-(3-methyl-phenyl)tetrazole in toluene. Conjugating corresponding 2° amines with 6-chloro-3-(m-tolyl)-[1,2,4]triazolo[4,3-b]pyridazine afforded the target triazolo-pyridazine-6-yl-substituted piperazines (5a-l). DPP-4 inhibition potential of these compounds was testified in silico and in nitro along with their insulinotropic activities in 832/13 INS-1 cells. H2O2 radical scavenging assay and MTT assay were conducted to assess the antioxidant and cytotoxicity of these compounds respectively. Molecular docking and ELISA based enzyme inhibition assay results revealed the strong inhibition potential of the target compounds. MTT assay results indicated a maximum dose of 2.5 nM (IC50 1.25 nM) could be used and above this level vital for the cells. Compounds 5a, 5c, 5g and 5i were found with excellent antioxidant and insulinotropic activity up to 99%.
|
Inhibition of human recombinant DPP4 (39 to 766 residues) using Ala-Pro-AFC as substrate incubated for 1 hr by fluorescence assay
|
Homo sapiens
|
1.0
nM
|
|
Journal : J Med Chem
Title : Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure.
Year : 2016
Volume : 59
Issue : 16
First Page : 7466
Last Page : 7477
Authors : Schnapp G, Klein T, Hoevels Y, Bakker RA, Nar H.
Abstract : The binding kinetics and thermodynamics of dipeptidyl peptidase (DPP)-4 inhibitors (gliptins) were investigated using surface plasmon resonance and isothermal titration calorimetry. Binding of gliptins to DPP-4 is a rapid electrostatically driven process. Off-rates were generally slow partly because of reversible covalent bond formation by some gliptins, and partly because of strong and extensive interactions. Binding of all gliptins is enthalpy-dominated due to strong ionic interactions and strong solvent-shielded hydrogen bonds. Using a congeneric series of molecules which represented the intermediates in the lead optimization program of linagliptin, the onset of slow binding kinetics and development of the thermodynamic repertoire were analyzed in the context of incremental changes of the chemical structures. All compounds rapidly associated, and therefore the optimization of affinity and residence time is highly correlated. The major contributor to the increasing free energy of binding was a strong increase of binding enthalpy, whereas entropic contributions remained low and constant despite significant addition of lipophilicity.
|
Binding affinity to human recombinant DPP4 (39 to 766 residues) by surface plasmon resonance analysis
|
Homo sapiens
|
0.0066
nM
|
|
Journal : J Med Chem
Title : Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure.
Year : 2016
Volume : 59
Issue : 16
First Page : 7466
Last Page : 7477
Authors : Schnapp G, Klein T, Hoevels Y, Bakker RA, Nar H.
Abstract : The binding kinetics and thermodynamics of dipeptidyl peptidase (DPP)-4 inhibitors (gliptins) were investigated using surface plasmon resonance and isothermal titration calorimetry. Binding of gliptins to DPP-4 is a rapid electrostatically driven process. Off-rates were generally slow partly because of reversible covalent bond formation by some gliptins, and partly because of strong and extensive interactions. Binding of all gliptins is enthalpy-dominated due to strong ionic interactions and strong solvent-shielded hydrogen bonds. Using a congeneric series of molecules which represented the intermediates in the lead optimization program of linagliptin, the onset of slow binding kinetics and development of the thermodynamic repertoire were analyzed in the context of incremental changes of the chemical structures. All compounds rapidly associated, and therefore the optimization of affinity and residence time is highly correlated. The major contributor to the increasing free energy of binding was a strong increase of binding enthalpy, whereas entropic contributions remained low and constant despite significant addition of lipophilicity.
|
Binding affinity to human recombinant DPP4 (39 to 766 residues) at 5 uM by isothermal titration calorimetry
|
Homo sapiens
|
5.3
nM
|
|
Journal : J Med Chem
Title : Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure.
Year : 2016
Volume : 59
Issue : 16
First Page : 7466
Last Page : 7477
Authors : Schnapp G, Klein T, Hoevels Y, Bakker RA, Nar H.
Abstract : The binding kinetics and thermodynamics of dipeptidyl peptidase (DPP)-4 inhibitors (gliptins) were investigated using surface plasmon resonance and isothermal titration calorimetry. Binding of gliptins to DPP-4 is a rapid electrostatically driven process. Off-rates were generally slow partly because of reversible covalent bond formation by some gliptins, and partly because of strong and extensive interactions. Binding of all gliptins is enthalpy-dominated due to strong ionic interactions and strong solvent-shielded hydrogen bonds. Using a congeneric series of molecules which represented the intermediates in the lead optimization program of linagliptin, the onset of slow binding kinetics and development of the thermodynamic repertoire were analyzed in the context of incremental changes of the chemical structures. All compounds rapidly associated, and therefore the optimization of affinity and residence time is highly correlated. The major contributor to the increasing free energy of binding was a strong increase of binding enthalpy, whereas entropic contributions remained low and constant despite significant addition of lipophilicity.
|
Inhibition of M1 receptor (unknown origin)
|
Homo sapiens
|
300.0
nM
|
|
Journal : J Med Chem
Title : Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure.
Year : 2016
Volume : 59
Issue : 16
First Page : 7466
Last Page : 7477
Authors : Schnapp G, Klein T, Hoevels Y, Bakker RA, Nar H.
Abstract : The binding kinetics and thermodynamics of dipeptidyl peptidase (DPP)-4 inhibitors (gliptins) were investigated using surface plasmon resonance and isothermal titration calorimetry. Binding of gliptins to DPP-4 is a rapid electrostatically driven process. Off-rates were generally slow partly because of reversible covalent bond formation by some gliptins, and partly because of strong and extensive interactions. Binding of all gliptins is enthalpy-dominated due to strong ionic interactions and strong solvent-shielded hydrogen bonds. Using a congeneric series of molecules which represented the intermediates in the lead optimization program of linagliptin, the onset of slow binding kinetics and development of the thermodynamic repertoire were analyzed in the context of incremental changes of the chemical structures. All compounds rapidly associated, and therefore the optimization of affinity and residence time is highly correlated. The major contributor to the increasing free energy of binding was a strong increase of binding enthalpy, whereas entropic contributions remained low and constant despite significant addition of lipophilicity.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.15
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
14.36
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
8.415
%
|
|
Title : Identification of inhibitors of SARS-Cov2 M-Pro enzymatic activity using a small molecule repurposing screen
Year : 2020
Authors : Maria Kuzikov, Elisa Costanzi, Jeanette Reinshagen, Francesca Esposito, Laura Vangeel, Markus Wolf, Bernhard Ellinger, Carsten Claussen, Gerd Geisslinger, Angela Corona, Daniela Iaconis, Carmine Talarico, Candida Manelfi, Rolando Cannalire, Giulia Rossetti, Jonas Gossen, Simone Albani, Francesco Musiani, Katja Herzog, Yang Ye, Barbara Giabbai, Nicola Demitri, Dirk Jochmans, Steven De Jonghe, Jasper Rymenants, Vincenzo Summa, Enzo Tramontano, Andrea R. Beccari, Pieter Leyssen, Paola Storici, Johan Neyts, Philip Gribbon, and Andrea Zaliani
Abstract : Compound repurposing is an important strategy being pursued in the identification of effective treatment against the SARS-CoV-2 infection and COVID-19 disease. In this regard, SARS-CoV-2 main protease (M-Pro), also termed 3CL-Pro, is an attractive drug target as it plays a central role in viral replication by processing the viral polyprotein into 11 non-structural proteins. We report the results of a screening campaign involving ca 8.7 K compounds containing marketed drugs, clinical and preclinical candidates, and chemicals regarded as safe in humans. We confirmed previously reported inhibitors of 3CL-Pro, but we have also identified 68 compounds with IC50 lower than 1 uM and 127 compounds with IC50 lower than 5 uM. Profiling showed 67% of confirmed hits were selective (> 5 fold) against other Cys- and Ser- proteases (Chymotrypsin and Cathepsin-L) and MERS 3CL-Pro. Selected compounds were also analysed in their binding characteristics.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.26
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.05
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.26
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
0.1
%
|
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of VERO-6 cells at 10 uM after 48 hours exposure to 0.01 MOI SARS CoV-2 virus by high content imaging
|
Chlorocebus sabaeus
|
-0.05
%
|
|
Title : Cytopathic SARS-Cov2 screening on VERO-E6 cells in a large repurposing effort
Year : 2020
Authors : Andrea Zaliani, Laura Vangeel, Jeanette Reinshagen, Daniela Iaconis, Maria Kuzikov, Oliver Keminer, Markus Wolf, Bernhard Ellinger, Francesca Esposito, Angela Corona, Enzo Tramontano, Candida Manelfi, Katja Herzog, Dirk Jochmans, Steven De Jonghe, Winston Chiu, Thibault Francken, Joost Schepers, Caroline Collard, Kayvan Abbasi, Carsten Claussen , Vincenzo Summa, Andrea R. Beccari, Johan Neyts, Philip Gribbon and Pieter Leyssen
Abstract : Worldwide, there are intensive efforts to identify repurposed drugs as potential therapies against SARS-CoV-2 infection and the associated COVID-19 disease. To date, the anti-inflammatory drug dexamethasone and (to a lesser extent) the RNA-polymerase inhibitor remdesivir have been shown to be effective in reducing mortality and patient time to recovery, respectively, in patients. Here, we report the results of a phenotypic screening campaign within an EU-funded project (H2020-EXSCALATE4COV) aimed at extending the repertoire of anti-COVID therapeutics through repurposing of available compounds and highlighting compounds with new mechanisms of action against viral infection. We screened 8702 molecules from different repurposing libraries, to reveal 110 compounds with an anti-cytopathic IC50 < 20 µM. From this group, 18 with a safety index greater than 2 are also marketed drugs, making them suitable for further study as potential therapies against COVID-19. Our result supports the idea that a systematic approach to repurposing is a valid strategy to accelerate the necessary drug discovery process.
