|
In vitro inhibition of human DPP-4 activity
|
Homo sapiens
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (3R)-4-[(3R)-3-Amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one, a selective dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.
Year : 2007
Volume : 17
Issue : 1
First Page : 49
Last Page : 52
Authors : Biftu T, Feng D, Qian X, Liang GB, Kieczykowski G, Eiermann G, He H, Leiting B, Lyons K, Petrov A, Sinha-Roy R, Zhang B, Scapin G, Patel S, Gao YD, Singh S, Wu J, Zhang X, Thornberry NA, Weber AE.
Abstract : Replacement of the triazolopiperazine ring of sitagliptin (DPP-4 IC(50)=18nM) with 3-(2,2,2-trifluoroethyl)-1,4-diazepan-2-one gave dipeptidyl peptidase IV (DPP-4) inhibitor 1 which is potent (DPP-4 IC(50)=2.6nM), selective, and efficacious in an oral glucose tolerance test in mice. It was selected for extensive preclinical development as a potential back-up candidate to sitagliptin.
|
Inhibition of DPP4
|
None
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Rational design of a novel, potent, and orally bioavailable cyclohexylamine DPP-4 inhibitor by application of molecular modeling and X-ray crystallography of sitagliptin.
Year : 2007
Volume : 17
Issue : 12
First Page : 3384
Last Page : 3387
Authors : Biftu T, Scapin G, Singh S, Feng D, Becker JW, Eiermann G, He H, Lyons K, Patel S, Petrov A, Sinha-Roy R, Zhang B, Wu J, Zhang X, Doss GA, Thornberry NA, Weber AE.
Abstract : Molecular modeling was used to design a rigid analog of sitagliptin 1. The X-ray crystal structure of sitagliptin bound to DPP-4 suggested that the central beta-amino butyl amide moiety could be replaced with a cyclohexylamine group. This was confirmed by structural analysis and the resulting analog 2a was synthesized and found to be a potent DPP-4 inhibitor (IC(50)=21 nM) with excellent in vivo activity and pharmacokinetic profile.
|
Inhibition of DPP4 activity
|
Homo sapiens
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Triazolopiperazine-amides as dipeptidyl peptidase IV inhibitors: close analogs of JANUVIA (sitagliptin phosphate).
Year : 2007
Volume : 17
Issue : 12
First Page : 3373
Last Page : 3377
Authors : Kim D, Kowalchick JE, Edmondson SD, Mastracchio A, Xu J, Eiermann GJ, Leiting B, Wu JK, Pryor KD, Patel RA, He H, Lyons KA, Thornberry NA, Weber AE.
Abstract : A series of beta-aminoamides bearing triazolopiperazines has been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. Efforts at optimization of the beta-aminoamide series, which ultimately led to the discovery of JANUVIA (sitagliptin phosphate, compound 1), are described.
|
Inhibition of DPP4
|
None
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Modeling assisted rational design of novel, potent, and selective pyrrolopyrimidine DPP-4 inhibitors.
Year : 2007
Volume : 17
Issue : 14
First Page : 3877
Last Page : 3879
Authors : Gao YD, Feng D, Sheridan RP, Scapin G, Patel SB, Wu JK, Zhang X, Sinha-Roy R, Thornberry NA, Weber AE, Biftu T.
Abstract : Molecular modeling was used to improve potency of the cyclohexylamine series. In addition, a 3-D QSAR method was used to gain insight for reducing off-target DPP-8/9 activities. Compounds 3, 4, and 5 were synthesized and found to be potent DPP-4 inhibitors, in particular 4 and 5 are designed to be highly selective against off-target DASH enzymes while maintaining potency on DPP-4.
|
Inhibition of DPP4
|
None
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis, and biological evaluation of triazolopiperazine-based beta-amino amides as potent, orally active dipeptidyl peptidase IV (DPP-4) inhibitors.
Year : 2007
Volume : 17
Issue : 21
First Page : 5934
Last Page : 5939
Authors : Kowalchick JE, Leiting B, Pryor KD, Marsilio F, Wu JK, He H, Lyons KA, Eiermann GJ, Petrov A, Scapin G, Patel RA, Thornberry NA, Weber AE, Kim D.
Abstract : Various beta-amino amides containing triazolopiperazine heterocycles have been prepared and evaluated as potent, selective, orally active dipeptidyl peptidase IV (DPP-4) inhibitors. These compounds display excellent oral bioavailability and good overall pharmacokinetic profiles in preclinical species. Moreover, in vivo efficacy in an oral glucose tolerance test in lean mice is demonstrated.
|
Inhibition of DPP4
|
None
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : The many roles for fluorine in medicinal chemistry.
Year : 2008
Volume : 51
Issue : 15
First Page : 4359
Last Page : 4369
Authors : Hagmann WK.
|
Inhibition of DPP4
|
None
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibitors of dipeptidyl peptidase 8 and dipeptidyl peptidase 9. Part 1: identification of dipeptide derived leads.
Year : 2008
Volume : 18
Issue : 14
First Page : 4154
Last Page : 4158
Authors : Van der Veken P, De Meester I, Dubois V, Soroka A, Van Goethem S, Maes MB, Brandt I, Lambeir AM, Chen X, Haemers A, Scharpé S, Augustyns K.
Abstract : Dipeptide derivatives bearing various P2 residues and pyrrolidine derivatives as P1 mimics were evaluated in order to identify lead structures for the development of DPP8 and DPP9 inhibitors. Structure-activity-relationship data obtained in this way led to the preparation of a series of alpha-aminoacyl ((2S, 4S)-4-azido-2-cyanopyrrolidines). These compounds were shown to be nanomolar DPP8/9 inhibitors with modest overall selectivity toward DPP IV and DPP II.
|
Inhibition of human DPP4 expressed in baculovirus system
|
Homo sapiens
|
18.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : A three-dimensional pharmacophore model for dipeptidyl peptidase IV inhibitors.
Year : 2008
Volume : 43
Issue : 8
First Page : 1603
Last Page : 1611
Authors : Lu IL, Tsai KC, Chiang YK, Jiaang WT, Wu SH, Mahindroo N, Chien CH, Lee SJ, Chen X, Chao YS, Wu SY.
Abstract : Dipeptidyl peptidase IV (DPP-IV) is a valid drug target for type-2 diabetes and DPP-IV inhibitors have been proven to efficiently improve glucose tolerance. In our study, 3D pharmacophore models were generated using a training set of 22 DPP-IV inhibitors. The best model consisted of important chemical features and mapped well into the active site of DPP-IV. The model gave high correlation coefficients of 0.97 and 0.84 for the training set and the test set, respectively, showing its good predictive ability for biological activity. Furthermore, the pharmacophore model demonstrated the capability to retrieve inhibitors from database with a high enrichment factor of 42.58. All results suggest that the model provides a useful tool for designing novel DPP-IV inhibitors.
|
Inhibition of DPP4 in human Caco-2 cells after 60 mins by fluorimetry assay
|
Homo sapiens
|
110.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and biological evaluation of pyrazoline analogues with beta-amino acyl group as dipeptidyl peptidase IV inhibitors.
Year : 2008
Volume : 43
Issue : 9
First Page : 1889
Last Page : 1902
Authors : Jun MA, Park WS, Kang SK, Kim KY, Kim KR, Rhee SD, Bae MA, Kang NS, Sohn SK, Kim SG, Lee JO, Lee DH, Cheon HG, Kim SS, Ahn JH.
Abstract : A series of pyrazoline derivatives with beta-amino acyl group were synthesized and evaluated for their ability to inhibit dipeptidyl peptidase IV. Several pyrazoline derivatives exhibited submicromolar inhibitory activities against DPP-IV. X-ray co-crystal structure of initial hit compound 1h was determined. Among this series, carboxylic acid substituted pyrazoline derivative 2u was the most active and greatly decreased the inhibitory activity toward CYP3A4 enzyme.
|
Inhibition of human DPP4
|
Homo sapiens
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Novel trans-2-aryl-cyclopropylamine analogues as potent and selective dipeptidyl peptidase IV inhibitors.
Year : 2009
Volume : 17
Issue : 6
First Page : 2388
Last Page : 2399
Authors : Tsai TY, Hsu T, Chen CT, Cheng JH, Yeh TK, Chen X, Huang CY, Chang CN, Yeh KC, Hsieh SH, Chien CH, Chang YW, Huang CH, Huang YW, Huang CL, Wu SH, Wang MH, Lu CT, Chao YS, Jiaang WT.
Abstract : A series of trans-2-aryl-cyclopropylamine derived compounds were synthesized and evaluated their biological activities against DPP-IV. The structure-activity relationships (SAR) led to the discovery of novel series of DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. The studies identified a potent and selective DPP-IV inhibitor 24b, which exhibited the ability to both significantly inhibit plasma DPP-IV activity in rats and improve glucose tolerance in lean mice and diet induced obese mice.
|
Inhibition of DPP4
|
None
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Rational design and synthesis of potent and long-lasting glutamic acid-based dipeptidyl peptidase IV inhibitors.
Year : 2009
Volume : 19
Issue : 7
First Page : 1908
Last Page : 1912
Authors : Tsai TY, Hsu T, Chen CT, Cheng JH, Chiou MC, Huang CH, Tseng YJ, Yeh TK, Huang CY, Yeh KC, Huang YW, Wu SH, Wang MH, Chen X, Chao YS, Jiaang WT.
Abstract : A series of (2S)-cyanopyrrolidines with glutamic acid derivatives at the P2 site have been prepared and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV). The structure-activity relationships (SAR) led to the discovery of potent 3-substituted glutamic acid analogues, providing enhanced chemical stability and excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. Compound 13f exhibited the ability to both significantly decrease the glucose excursion and inhibit plasma DPP-IV activity.
|
Inhibition of DPP4
|
None
|
18.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis and evaluation of structurally constrained imidazolidin derivatives as potent dipeptidyl peptidase IV inhibitors.
Year : 2009
Volume : 44
Issue : 8
First Page : 3318
Last Page : 3322
Authors : Wang L, Zhang B, Ji J, Li B, Yan J, Zhang W, Wu Y, Wang X.
Abstract : To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine derivatives with constrained imidazolidin ring and tested their activities against DPP-IV. Most of them exhibited submicromolar inhibitory activities against DPP-IV. The most potent compound among these is (S)-1-(2-(2-(3-(3,4-dimethoxyphenyl)-2-oxoimidazolidin-1-yl)ethyl-amino)acetyl)pyrrolidine-2-carbonitrile (6n), which is a 2 nM DPP-IV inhibitor.
|
Inhibition of DPP4
|
None
|
30.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.
Year : 2010
Volume : 20
Issue : 12
First Page : 3596
Last Page : 3600
Authors : Yeh TK, Tsai TY, Hsu T, Cheng JH, Chen X, Song JS, Shy HS, Chiou MC, Chien CH, Tseng YJ, Huang CY, Yeh KC, Huang YL, Huang CH, Huang YW, Wang MH, Tang HK, Chao YS, Chen CT, Jiaang WT.
Abstract : A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure-activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC(50)>20 microM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats.
|
Ex vivo inhibition of DPP4 in rat plasma at 3 mg/kg, po after 30 mins
|
Rattus norvegicus
|
30.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.
Year : 2010
Volume : 20
Issue : 12
First Page : 3596
Last Page : 3600
Authors : Yeh TK, Tsai TY, Hsu T, Cheng JH, Chen X, Song JS, Shy HS, Chiou MC, Chien CH, Tseng YJ, Huang CY, Yeh KC, Huang YL, Huang CH, Huang YW, Wang MH, Tang HK, Chao YS, Chen CT, Jiaang WT.
Abstract : A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure-activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC(50)>20 microM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats.
|
Ex vivo inhibition of DPP4 in rat plasma at 3 mg/kg, po after 8 hrs
|
Rattus norvegicus
|
20.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.
Year : 2010
Volume : 20
Issue : 12
First Page : 3596
Last Page : 3600
Authors : Yeh TK, Tsai TY, Hsu T, Cheng JH, Chen X, Song JS, Shy HS, Chiou MC, Chien CH, Tseng YJ, Huang CY, Yeh KC, Huang YL, Huang CH, Huang YW, Wang MH, Tang HK, Chao YS, Chen CT, Jiaang WT.
Abstract : A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure-activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC(50)>20 microM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats.
|
Inhibition of DPP4 in presence of 50% human serum
|
None
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.
Year : 2010
Volume : 20
Issue : 12
First Page : 3596
Last Page : 3600
Authors : Yeh TK, Tsai TY, Hsu T, Cheng JH, Chen X, Song JS, Shy HS, Chiou MC, Chien CH, Tseng YJ, Huang CY, Yeh KC, Huang YL, Huang CH, Huang YW, Wang MH, Tang HK, Chao YS, Chen CT, Jiaang WT.
Abstract : A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure-activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC(50)>20 microM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats.
|
Inhibition of DPP4 in presence of 50% rat serum
|
None
|
46.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : (2S,4S)-1-[2-(1,1-dimethyl-3-oxo-3-pyrrolidin-1-yl-propylamino)acetyl]-4-fluoro-pyrrolidine-2-carbonitrile: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.
Year : 2010
Volume : 20
Issue : 12
First Page : 3596
Last Page : 3600
Authors : Yeh TK, Tsai TY, Hsu T, Cheng JH, Chen X, Song JS, Shy HS, Chiou MC, Chien CH, Tseng YJ, Huang CY, Yeh KC, Huang YL, Huang CH, Huang YW, Wang MH, Tang HK, Chao YS, Chen CT, Jiaang WT.
Abstract : A series of 2-[3-[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]-based DPP-IV inhibitors with various monocyclic amines were synthesized. The structure-activity relationships (SAR) led to the discovery of potent DPP-IV inhibitors, having IC(50) values of <100 nM with excellent selectivity over the closely related enzymes, DPP-II, DPP8, DPP9 and FAP (IC(50)>20 microM). Of these compounds, the analogues 12a, 12h and 12i exhibited a long-lasting ex vivo DPP-IV inhibition in rats.
|
Inhibition of human recombinant His-tagged DPP4 expressed in insect cells
|
Homo sapiens
|
23.0
nM
|
|
Journal : J. Med. Chem.
Title : Substituted 4-carboxymethylpyroglutamic acid diamides as potent and selective inhibitors of fibroblast activation protein.
Year : 2010
Volume : 53
Issue : 18
First Page : 6572
Last Page : 6583
Authors : Tsai TY, Yeh TK, Chen X, Hsu T, Jao YC, Huang CH, Song JS, Huang YC, Chien CH, Chiu JH, Yen SC, Tang HK, Chao YS, Jiaang WT.
Abstract : Fibroblast activation protein (FAP) belongs to the prolyl peptidase family. FAP inhibition is expected to become a new antitumor target. Most known FAP inhibitors often resemble the dipeptide cleavage products, with a boroproline at the P1 site; however, these inhibitors also inhibit DPP-IV, DPP-II, DPP8, and DPP9. Potent and selective FAP inhibitor is needed in evaluating that FAP as a therapeutic target. Therefore, it is important to develop selective FAP inhibitors for the use of target validation. To achieve this, optimization of the nonselective DPP-IV inhibitor 8 led to the discovery of a new class of substituted 4-carboxymethylpyroglutamic acid diamides as FAP inhibitors. SAR studies resulted in a number of FAP inhibitors having IC(50) of <100 nM with excellent selectivity over DPP-IV, DPP-II, DPP8, and DPP9 (IC(50) > 100 μM). Compounds 18a, 18b, and 19 are the only known potent and selective FAP inhibitors, which prompts us to further study the physiological role of FAP.
|
Inhibition of human seminal fluid DPP4
|
Homo sapiens
|
11.0
%
|
|
Journal : Eur. J. Med. Chem.
Title : Synthesis, biological assay in vitro and molecular docking studies of new imidazopyrazinone derivatives as potential dipeptidyl peptidase IV inhibitors.
Year : 2010
Volume : 45
Issue : 11
First Page : 4953
Last Page : 4962
Authors : Zhu Y, Xia S, Zhu M, Yi W, Cheng J, Song G, Li Z, Lu P.
Abstract : A series of novel imidazopyrazinone derivatives were synthesized and evaluated with regard to their ability to inhibit dipeptidyl peptidase IV (DPP-IV) in vitro. Of these compounds (2R)-4-oxo-4-[2-(3-carbamoylbenzyl)-hexahydro-3-oxoimidazo [1,5-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine fumaric acid (17h, IC(50)=78 nM) was shown to effectively inhibit the activity of the dipeptidyl peptidase IV enzyme. Molecular docking studies were also performed to illustrate the binding mode of compounds 15c and 17h. Favorable interactions were identified from the binding of inhibitor 15c with DPP-IV. By analogy to the binding mode of compound 15c, it seems that the introduction of a substituted benzyl moiety onto the imidazopyrazinone could remarkably improve the inhibitory activity of compound 17h.
|
Inhibition of human recombinant DPP4 after 60 mins by fluorescence plate reader
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of β-aminoacyl containing thiazolidine derivatives as potent and selective dipeptidyl peptidase IV inhibitors.
Year : 2011
Volume : 21
Issue : 5
First Page : 1366
Last Page : 1370
Authors : Park WS, Kang SK, Jun MA, Shin MS, Kim KY, Rhee SD, Bae MA, Kim MS, Kim KR, Kang NS, Yoo SE, Lee JO, Song DH, Silinski P, Schneider SE, Ahn JH, Kim SS.
Abstract : A series of β-aminoacyl containing thiazolidine derivatives was synthesized and evaluated for their ability to inhibit DPP-IV. Several thiazolidine derivatives with an acid moiety were found to be potent DPP-IV inhibitors. Among them, compound 2da is the most active in this series with an IC(50) value of 1 nM, and it showed excellent selectivity over DPP-IV related enzymes including DPP-2, DPP-8, and DPP-9. Compound 2da is chemically and metabolically stable, and showed no CYP inhibition, hERG binding or cytotoxicity. Compound 2db, an ester prodrug of 2da, showed good in vivo DPP-IV inhibition after oral administration in rat and dog models.
|
Inhibition of DPP4
|
None
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and evaluation of [(1R)-1-amino-2-(2,5-difluorophenyl)ethyl]cyclohexanes and 4-[(1R)-1-amino-2-(2,5-difluorophenyl)ethyl]piperidines as DPP-4 inhibitors.
Year : 2011
Volume : 21
Issue : 6
First Page : 1880
Last Page : 1886
Authors : Chen P, Caldwell CG, Ashton W, Wu JK, He H, Lyons KA, Thornberry NA, Weber AE.
Abstract : A series of 4-amino cyclohexanes and 4-substituted piperidines were prepared and evaluated for inhibition of DPP-4. Analog 20q displayed both good DPP-4 potency and selectivity against other proteases, while derivative 20k displayed long half life and modest oral bioavailability in rat. The most potent analog, 3-(5-aminocarbonylpyridyl piperidine 53j, displayed excellent DPP-4 activity with good selectivity versus other proline enzymes.
|
Inhibition of human DPP4 assessed as hydrolytic reaction of Ala-Pro-AMC
|
Homo sapiens
|
19.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of potent dipeptidyl peptidase IV inhibitors derived from β-aminoamides bearing substituted [1,2,3]-triazolopiperidines for the treatment of type 2 diabetes.
Year : 2011
Volume : 21
Issue : 6
First Page : 1731
Last Page : 1735
Authors : Shan Z, Peng M, Fan H, Lu Q, Lu P, Zhao C, Chen Y.
Abstract : A series of novel [1,2,3]-triazolopiperidine derivatives 5a-5y were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-4) for the treatment of type 2 diabetes, most of the compounds exhibited excellent in vitro potency (IC(50)<50n M) against DPP-4. Among these, compound 5d with potent in vitro activity against DPP-4 and good pharmacokinetic profiles exhibited pronounced in vivo efficacy in an oral glucose tolerance test (OGTT) in ICR mice. On the base of these properties, compound 5d was selected as a potential new candidate for the treatment of type 2 diabetes.
|
Inhibition of DPP4
|
None
|
40.0
nM
|
|
Journal : J. Med. Chem.
Title : Structure-activity relationship studies on isoindoline inhibitors of dipeptidyl peptidases 8 and 9 (DPP8, DPP9): is DPP8-selectivity an attainable goal?
Year : 2011
Volume : 54
Issue : 16
First Page : 5737
Last Page : 5746
Authors : Van Goethem S, Matheeussen V, Joossens J, Lambeir AM, Chen X, De Meester I, Haemers A, Augustyns K, Van der Veken P.
Abstract : This work represents the first directed study to identify modification points in the topology of a representative DPP8/9-inhibitor, capable of rendering selectivity for DPP8 over DPP9. The availability of a DPP8-selective compound would be highly instrumental for studying and untwining the biological roles of DPP8 and DPP9 and for the disambiguation of biological effects of nonselective DPP-inhibitors that have mainly been ascribed to blocking of DPPIV's action. The cell-permeable DPP8/9-inhibitor 7 was selected as a lead and dissected into several substructures that were modified separately for evaluating their potential to contribute to selectivity. The obtained results, together with earlier work from our group, clearly narrow down the most probable DPP8-selectivity imparting modification points in DPP8/9 inhibitors to parts of space that are topologically equivalent to the piperazine ring system in 7. This information can be considered of high value for future design of compounds with maximal DPP8 selectivity.
|
Inhibition of DPP4 in human plasma assessed as formation of 7-amino-4-methylcoumarin from glycyl-L-proline 4-methylcoumaryl-7-amide by fluorescence assay
|
Homo sapiens
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem.
Title : 2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727): a potent, orally active dipeptidyl peptidase IV inhibitor without mechanism-based inactivation of CYP3A.
Year : 2011
Volume : 19
Issue : 18
First Page : 5490
Last Page : 5499
Authors : Nishio Y, Kimura H, Sawada N, Sugaru E, Horiguchi M, Ono M, Furuta Y, Sakai M, Masui Y, Otani M, Hashizuka T, Honda Y, Deguchi J, Nakagawa T, Nakahira H.
Abstract : We report on the identification of 2-({6-[(3R)-3-amino-3-methylpiperidine-1-yl]-1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-5H-pyrrolo[3,2-d]pyrimidine-5-yl}methyl)-4-fluorobenzonitrile (DSR-12727) (7a) as a potent and orally active DPP-4 inhibitor without mechanism-based inactivation of CYP3A. Compound 7a showed good DPP-4 inhibitory activity (IC(50)=1.1 nM), excellent selectivity against related peptidases and other off-targets, good pharmacokinetic and pharmacodynamic profile, great in vivo efficacy in Zucker-fatty rat, and no safety concerns both in vitro and in vivo.
|
Inhibition of human seminal plasma DPP4 assessed as pNA release from Gly-Pro-p-nitroanilide substrate pre-incubated with enzyme for 15 min prior to substrate addition by fluorescence technique
|
Homo sapiens
|
40.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Acylated Gly-(2-cyano)pyrrolidines as inhibitors of fibroblast activation protein (FAP) and the issue of FAP/prolyl oligopeptidase (PREP)-selectivity.
Year : 2012
Volume : 22
Issue : 10
First Page : 3412
Last Page : 3417
Authors : Ryabtsova O, Jansen K, Van Goethem S, Joossens J, Cheng JD, Lambeir AM, De Meester I, Augustyns K, Van der Veken P.
Abstract : A series of N-acylated glycyl-(2-cyano)pyrrolidines were synthesized with the aim of generating structure-activity relationship (SAR) data for this class of compounds as inhibitors of fibroblast activation protein (FAP). Specifically, the influence of (1) the choice of the N-acyl group and (2) structural modification of the 2-cyanopyrrolidine residue were investigated. The inhibitors displayed inhibitory potency in the micromolar to nanomolar range and showed good to excellent selectivity with respect to the proline selective dipeptidyl peptidases (DPPs) DPP IV, DPP9 and DPP II. Additionally, selectivity for FAP with respect to prolyl oligopeptidase (PREP) is reported. Not unexpectedly, the latter data suggest significant overlap in the pharmacophoric features that define FAP or PREP-inhibitory activity and underscore the importance of systematically evaluating the FAP/PREP-selectivity index for inhibitors of either of these two enzymes. Finally, this study forwards several compounds that can serve as leads or prototypic structures for future FAP-selective-inhibitor discovery.
|
Inhibition of DPP4 in human plasma using Gly-Pro-AMC as substrate by fluorimetric analysis
|
Homo sapiens
|
18.0
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 DPP4 in human Caco2 cells using H-Ala-Pro-7-amido-4-trifluoromethylcoumarin as substrate after 1 hr by fluorescence assay
|
Homo sapiens
|
19.0
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 human purified His-tagged DPP-4 assessed as cleavage of substrate using Gly-Pro-AMC chromogenic substrate after 60 mins by fluorescence spectrophotometry
|
Homo sapiens
|
24.83
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of novel benzyl-substituted (S)-phenylalanine derivatives as potent dipeptidyl peptidase 4 inhibitors.
Year : 2013
Volume : 21
Issue : 18
First Page : 5679
Last Page : 5687
Authors : Liu Y, Si M, Tang L, Shangguan S, Wu H, Li J, Wu P, Ma X, Liu T, Hu Y.
Abstract : A series of novel benzyl-substituted (S)-phenylalanine derivatives were synthesized and evaluated for their dipeptidyl peptidase 4 (DPP-4) inhibitory activity and selectivity. It was found that most synthesized target compounds were potent DPP-4 inhibitors with IC50 values in 3.79-25.52 nM, which were significantly superior to that of the marketed drug sitagliptin. Furthermore, the 4-fluorobenzyl substituted phenylalanine derivative 6g not only displayed the potent DPP-4 inhibition with an IC50 value of 3.79 nM, but also showed better selectivity against DPP-4 over other related enzymes including DPP-7, DPP-8, and DPP-9. In an oral glucose tolerance test (OGTT) in normal Sprague Dawley rats, compound 6g reduced blood glucose excursion in a dose-dependent manner.
|
Ex vivo inhibition of DPP4 in Sprague-Dawley rat plasma at 3 mg/kg, po after 8 hrs
|
Rattus norvegicus
|
30.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV.
Year : 2014
Volume : 24
Issue : 3
First Page : 731
Last Page : 736
Authors : Namoto K, Sirockin F, Ostermann N, Gessier F, Flohr S, Sedrani R, Gerhartz B, Trappe J, Hassiepen U, Duttaroy A, Ferreira S, Sutton JM, Clark DE, Fenton G, Beswick M, Baeschlin DK.
Abstract : The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat.
|
Ex vivo inhibition of DPP4 in Sprague-Dawley rat plasma at 3 mg/kg, po after 1 to 2 hrs
|
Rattus norvegicus
|
82.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV.
Year : 2014
Volume : 24
Issue : 3
First Page : 731
Last Page : 736
Authors : Namoto K, Sirockin F, Ostermann N, Gessier F, Flohr S, Sedrani R, Gerhartz B, Trappe J, Hassiepen U, Duttaroy A, Ferreira S, Sutton JM, Clark DE, Fenton G, Beswick M, Baeschlin DK.
Abstract : The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat.
|
Inhibition of human recombinant DPP4 (39 to 766)
|
Homo sapiens
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV.
Year : 2014
Volume : 24
Issue : 3
First Page : 731
Last Page : 736
Authors : Namoto K, Sirockin F, Ostermann N, Gessier F, Flohr S, Sedrani R, Gerhartz B, Trappe J, Hassiepen U, Duttaroy A, Ferreira S, Sutton JM, Clark DE, Fenton G, Beswick M, Baeschlin DK.
Abstract : The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat.
|
Inhibition of DPP4 (unknown origin)
|
Homo sapiens
|
7.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Discovery of C-(1-aryl-cyclohexyl)-methylamines as selective, orally available inhibitors of dipeptidyl peptidase IV.
Year : 2014
Volume : 24
Issue : 3
First Page : 731
Last Page : 736
Authors : Namoto K, Sirockin F, Ostermann N, Gessier F, Flohr S, Sedrani R, Gerhartz B, Trappe J, Hassiepen U, Duttaroy A, Ferreira S, Sutton JM, Clark DE, Fenton G, Beswick M, Baeschlin DK.
Abstract : The successful launches of dipeptidyl peptidase IV (DPP IV) inhibitors as oral anti-diabetics warrant and spur the further quest for additional chemical entities in this promising class of therapeutics. Numerous pharmaceutical companies have pursued their proprietary candidates towards the clinic, resulting in a large body of published chemical structures associated with DPP IV. Herein, we report the discovery of a novel chemotype for DPP IV inhibition based on the C-(1-aryl-cyclohexyl)-methylamine scaffold and its optimization to compounds which selectively inhibit DPP IV at low-nM potency and exhibit an excellent oral pharmacokinetic profile in the rat.
|
Inhibition of recombinant his6-tagged DPP4 (unknown origin) expressed in baculovirus expression system using Ala-pro-AMC as substrate by fluorometric analysis
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of hetero-aromatic moieties substituted pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors.
Year : 2014
Volume : 75
First Page : 111
Last Page : 122
Authors : Ji X, Su M, Wang J, Deng G, Deng S, Li Z, Tang C, Li J, Li J, Zhao L, Jiang H, Liu H.
Abstract : A series of novel hetero-aromatic moieties substituted α-amino pyrrole-2-carbonitrile derivatives was designed and synthesized based on structure-activity relationships (SARs) of pyrrole-2-carbonitrile inhibitors. All compounds demonstrated good dipeptidyl peptidase IV (DPP4) inhibitory activities (IC50 = 0.004-113.6 μM). Moreover, compounds 6h (IC50 = 0.004 μM) and 6n (IC50 = 0.01 μM) showed excellent inhibitory activities against DPP4, good selectivity (compound 6h, selective ratio: DPP8/DPP4 = 450.0; DPP9/DPP4 = 375.0; compound 6n, selective ratio: DPP8/DPP4 = 470.0; DPP9/DPP4 = 750.0) and good efficacy in an oral glucose tolerance test in ICR mice. Furthermore, compounds 6h and 6n demonstrated moderate PK properties (compound 6h, F% = 37.8%, t1/2 = 1.45 h; compound 6n, F% = 16.8%, t1/2 = 3.64 h).
|
Inhibition of DPP4 (unknown origin)
|
Homo sapiens
|
19.0
nM
|
|
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 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 human DPP-4 expressed in baculovirus expression system using H-Gly-Pro-AMC as substrate after 30 mins by fluorometric analysis
|
Homo sapiens
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological evaluation of novel aminomethyl-piperidones based DPP-IV inhibitors.
Year : 2014
Volume : 24
Issue : 8
First Page : 1918
Last Page : 1922
Authors : Jadav P, Bahekar R, Shah SR, Patel D, Joharapurkar A, Jain M, Sairam KV, Singh PK.
Abstract : A series of novel aminomethyl-piperidones were designed and evaluated as potential DPP-IV inhibitors. Optimized analogue 12v ((4S,5S)-5-(aminomethyl)-1-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-4-(2,5-difluorophenyl)piperidin-2-one) showed excellent in vitro potency and selectivity for DPP-IV over other serine proteases. The lead compound 12v showed potent and long acting antihyperglycemic effects (in vivo), along with improved pharmacokinetic profile.
|
Competitive reversible inhibition of DPP4 (unknown origin)
|
Homo sapiens
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : Omarigliptin (MK-3102): a novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes.
Year : 2014
Volume : 57
Issue : 8
First Page : 3205
Last Page : 3212
Authors : Biftu T, Sinha-Roy R, Chen P, Qian X, Feng D, Kuethe JT, Scapin G, Gao YD, Yan Y, Krueger D, Bak A, Eiermann G, He J, Cox J, Hicks J, Lyons K, He H, Salituro G, Tong S, Patel S, Doss G, Petrov A, Wu J, Xu SS, Sewall C, Zhang X, Zhang B, Thornberry NA, Weber AE.
Abstract : In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.
|
Inhibition of human recombinant his6-tagged DPP4 using Ala-Pro-AMC as substrate by continuous fluorometric method
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives as potent inhibitors of dipeptidyl peptidase-4: design, synthesis, biological evaluation, and molecular modeling.
Year : 2014
Volume : 22
Issue : 23
First Page : 6684
Last Page : 6693
Authors : Wang S, Su M, Wang J, Li Z, Zhang L, Ji X, Li J, Li J, Liu H.
Abstract : A series of (R)-3-amino-1-((3aS,7aS)-octahydro-1H-indol-1-yl)-4-(2,4,5-trifluorophenyl)butan-1-one derivatives was designed, synthesized, and evaluated as novel inhibitors of dipeptidyl peptidase-4 (DPP-4) for the treatment of type 2 diabetes. Most of the synthesized compounds demonstrated good inhibition activities against DPP-4. Among these, compounds 3e, 4c, 4l, and 4n exhibited prominent inhibition activities against DPP-4, with IC50s of 0.07, 0.07, 0.14, and 0.17μM, respectively. The possible binding modes of compounds 3e and 4n with dipeptidyl peptidase-4 were also explored by molecular docking simulation. These potent DPP-4 inhibitors were optimized for the absorption, distribution, metabolism, and excretion (ADME) properties, and compound 4n displayed an attractive pharmacokinetic profile (F=96.3%, t1/2=10.5h).
|
Inhibition of human DPP-4 using H-Gly-Pro-para-Nitroanilide as substrate incubated for 20 mins prior to substrate addition measured after 30 mins by spectrophotometry
|
Homo sapiens
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure based virtual screening of MDPI database: discovery of structurally diverse and novel DPP-IV inhibitors.
Year : 2014
Volume : 24
Issue : 15
First Page : 3447
Last Page : 3451
Authors : Tanwar O, Tanwar L, Shaquiquzzaman M, Alam MM, Akhter M.
Abstract : Inhibition of dipeptidyl peptidase IV (DPP-IV) has been emerged as a promising approach for the treatment of type 2 diabetes (T2D). Structure based virtual screening (SBVS) of Molecular Diversity Preservation International (MDPI) database was performed using Glide and Gold against DPP-IV enzyme. Six promising hits were identified and tested for DPP-IV inhibition. Three compounds were found to be active at low micromolar concentration. The 3-(1-hydrazinyl-1-(phenylamino)ethyl)-4-hydroxy-1-methylquinolin-2(1H)-one (compound A) was found to be the most potent hit with an IC50 of 0.73 μM. These three compounds (A, B and D) were then assessed for their glucose lowering effects in glucose fed hyperglycemic female Wistar rats. The glucose lowering effects of compounds also confirms their potential as anti-diabetic agents. The present study demonstrates a successful utilization of in silico SBVS tools in identification of novel and potential DPP-IV inhibitor.
|
Inhibition of human recombinant DPP4 pre-incubated with compound for 15 mins before substrate addition by luminescence assay
|
Homo sapiens
|
29.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Imigliptin, a Novel Selective DPP-4 Inhibitor for the Treatment of Type 2 Diabetes.
Year : 2014
Volume : 5
Issue : 8
First Page : 921
Last Page : 926
Authors : Shu C, Ge H, Song M, Chen JH, Zhou H, Qi Q, Wang F, Ma X, Yang X, Zhang G, Ding Y, Zhou D, Peng P, Shih CK, Xu J, Wu F.
Abstract : We report our discovery of a novel series of potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Starting from a lead identified by scaffold-hopping approach, our discovery and development efforts were focused on exploring structure-activity relationships, optimizing pharmacokinetic profile, improving in vitro and in vivo efficacy, and evaluating safety profile. The selected candidate, Imigliptin, is now undergoing clinical trial.
|
Inhibition of DPP4 activity in C57BL/6 mouse at 3 mg/kg, po administered as single dose 30 mins before orally glucose challenge and measured 20 mins post oral glucose challenge by luminescence assay
|
Mus musculus
|
59.5
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Imigliptin, a Novel Selective DPP-4 Inhibitor for the Treatment of Type 2 Diabetes.
Year : 2014
Volume : 5
Issue : 8
First Page : 921
Last Page : 926
Authors : Shu C, Ge H, Song M, Chen JH, Zhou H, Qi Q, Wang F, Ma X, Yang X, Zhang G, Ding Y, Zhou D, Peng P, Shih CK, Xu J, Wu F.
Abstract : We report our discovery of a novel series of potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Starting from a lead identified by scaffold-hopping approach, our discovery and development efforts were focused on exploring structure-activity relationships, optimizing pharmacokinetic profile, improving in vitro and in vivo efficacy, and evaluating safety profile. The selected candidate, Imigliptin, is now undergoing clinical trial.
|
Antidiabetic activity in C57BL/6 mouse assessed as reduction in plasma glucose AUC (0 to 120 mins) at 3 mg/kg, po administered as single dose 30 mins before orally glucose challenge by oral glucose tolerance test
|
Mus musculus
|
59.0
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Discovery of Imigliptin, a Novel Selective DPP-4 Inhibitor for the Treatment of Type 2 Diabetes.
Year : 2014
Volume : 5
Issue : 8
First Page : 921
Last Page : 926
Authors : Shu C, Ge H, Song M, Chen JH, Zhou H, Qi Q, Wang F, Ma X, Yang X, Zhang G, Ding Y, Zhou D, Peng P, Shih CK, Xu J, Wu F.
Abstract : We report our discovery of a novel series of potent and selective dipeptidyl peptidase IV (DPP-4) inhibitors. Starting from a lead identified by scaffold-hopping approach, our discovery and development efforts were focused on exploring structure-activity relationships, optimizing pharmacokinetic profile, improving in vitro and in vivo efficacy, and evaluating safety profile. The selected candidate, Imigliptin, is now undergoing clinical trial.
|
Inhibition of human recombinant DPP4 expressed in baculovirus expression system using Ala-Pro-AMC as substrate by continuous fluorometric assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : Eur. J. Med. Chem.
Title : Design, synthesis and biological evaluation of 4-fluoropyrrolidine-2-carbonitrile and octahydrocyclopenta[b]pyrrole-2-carbonitrile derivatives as dipeptidyl peptidase IV inhibitors.
Year : 2014
Volume : 86
First Page : 242
Last Page : 256
Authors : Ji X, Xia C, Wang J, Su M, Zhang L, Dong T, Li Z, Wan X, Li J, Li J, Zhao L, Gao Z, Jiang H, Liu H.
Abstract : Based on the previous work in our group and the principle of computer-aided drug design, a series of novel β-amino pyrrole-2-carbonitrile derivatives was designed and synthesized. Compounds 8l and 9l were efficacious and selective DPP4 inhibitors resulting in decreased blood glucose in vivo. Compound 8l had moderate DPP4 inhibitory activity (IC50 = 0.05 μM) and good oral bioavailability (F = 53.2%). Compound 9l showed excellent DPP4 inhibitory activity (IC50 = 0.01 μM), good selectivity (selective ratio: DPP8/DPP4 = 898.00; DPP9/DPP4 = 566.00) against related peptidases, and good efficacy in an oral glucose tolerance tests in ICR mice and moderate PK profiles (F = 22.8%, t1/2 = 2.74 h). Moreover, compound 9l did not block hERG channel and exhibited no inhibition of liver metabolic enzymes such as CYP2C9.
|
Inhibition of DPP4 (unknown origin) at 1 uM pre-incubated for 1 hr before Gly-Pro-pNA substrate addition and measured 2 hrs post substrate addition
|
Homo sapiens
|
101.9
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and potent inhibitory activities of carboxybenzyl-substituted 8-(3-(R)-aminopiperidin-1-yl)-7-(2-chloro/cyanobenzyl)-3-methyl-3,7-dihydro-purine-2,6-diones as dipeptidyl peptidase IV (DPP-IV) inhibitors.
Year : 2015
Volume : 25
Issue : 9
First Page : 1872
Last Page : 1875
Authors : Mo DW, Dong S, Sun H, Chen JS, Pang JX, Xi BM, Chen WH.
Abstract : Fourteen 3-methyl-3,7-dihydro-purine-2,6-dione derivatives 1-14 bearing carboxybenzyl and 2-chloro/cyanobenzyl groups at the N-1 and N-7 positions, respectively, were synthesized as dipeptidyl peptidase IV (DPP-IV) inhibitors. These compounds were characterized on the basis of NMR ((1)H and (13)C) and ESI MS data. In vitro bioassay indicates that most of these compounds showed moderate to good inhibitory activities against DPP-IV. Among them, compound 13 (IC50=36 nM) exhibited comparable activity with a positive control, Sitagliptin (IC50=16 nM). In addition, the structure-activity relationship of these compounds is also briefly discussed.
|
Inhibition of DPP4 (unknown origin) pre-incubated for 1 hr before Gly-Pro-pNA substrate addition and measured 2 hrs post substrate addition
|
Homo sapiens
|
16.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and potent inhibitory activities of carboxybenzyl-substituted 8-(3-(R)-aminopiperidin-1-yl)-7-(2-chloro/cyanobenzyl)-3-methyl-3,7-dihydro-purine-2,6-diones as dipeptidyl peptidase IV (DPP-IV) inhibitors.
Year : 2015
Volume : 25
Issue : 9
First Page : 1872
Last Page : 1875
Authors : Mo DW, Dong S, Sun H, Chen JS, Pang JX, Xi BM, Chen WH.
Abstract : Fourteen 3-methyl-3,7-dihydro-purine-2,6-dione derivatives 1-14 bearing carboxybenzyl and 2-chloro/cyanobenzyl groups at the N-1 and N-7 positions, respectively, were synthesized as dipeptidyl peptidase IV (DPP-IV) inhibitors. These compounds were characterized on the basis of NMR ((1)H and (13)C) and ESI MS data. In vitro bioassay indicates that most of these compounds showed moderate to good inhibitory activities against DPP-IV. Among them, compound 13 (IC50=36 nM) exhibited comparable activity with a positive control, Sitagliptin (IC50=16 nM). In addition, the structure-activity relationship of these compounds is also briefly discussed.
|
Inhibition of human recombinant DPP4 using H-Gly-Pro-AMC substrate incubated for 15 mins by fluorescent AMC release assay
|
Homo sapiens
|
22.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Synthesis of New DPP-4 Inhibitors Based on a Novel Tricyclic Scaffold.
Year : 2015
Volume : 6
Issue : 3
First Page : 324
Last Page : 328
Authors : Schwehm C, Li J, Song H, Hu X, Kellam B, Stocks MJ.
Abstract : A novel molecular scaffold has been synthesized, and its synthesis and incorporation into new analogues of biologically active molecules will be discussed. A comparison of the inhibitory activity of these compounds to the known type-2 diabetes compound (sitagliptin) against dipeptidyl peptidase-4 (DPP-4) will be shown.
|
Inhibition of DPP4 extracted from human Caco2 cells using H-Gly-Pro-AMC substrate after 10 mins by fluorescence assay
|
Homo sapiens
|
19.0
nM
|
|
Journal : ACS Med. Chem. Lett.
Title : Design, Synthesis, and Pharmacological Evaluation of Fused β-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors.
Year : 2015
Volume : 6
Issue : 5
First Page : 602
Last Page : 606
Authors : Jiang T, Zhou Y, Chen Z, Sun P, Zhu J, Zhang Q, Wang Z, Shao Q, Jiang X, Li B, Chen K, Jiang H, Wang H, Zhu W, Shen J.
Abstract : Dipeptidyl peptidase-4 (DPP-4) inhibitors are accepted as a favorable class of agents for the treatment of type 2 diabetes. Herein, a series of fused β-homophenylalanine derivatives as novel DPP-4 inhibitors were designed, synthesized, and evaluated for their inhibitory activities against DPP-4. Most of them displayed excellent DPP-4 inhibitory activities and good selectivity. Among them, 9aa, 18a, and 18m also showed good efficacy in an oral glucose tolerance test (OGTT) in ICR mice. Moreover, when dosed 8 h prior to glucose challenge, 18m showed significantly greater potency than sitagliptin. It thus provides potential candidates for the further development into potent drugs targeting DPP-4.
|
Anti-diabetic effect in ICR mouse assessed as plasma glucose lowering effect at 10 mg/kg, po treated 1 hr before 2.5 mg/kg, po glucose load by Oral glucose tolerance test relative to control
|
Mus musculus
|
40.0
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Design, Synthesis, and Pharmacological Evaluation of Fused β-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors.
Year : 2015
Volume : 6
Issue : 5
First Page : 602
Last Page : 606
Authors : Jiang T, Zhou Y, Chen Z, Sun P, Zhu J, Zhang Q, Wang Z, Shao Q, Jiang X, Li B, Chen K, Jiang H, Wang H, Zhu W, Shen J.
Abstract : Dipeptidyl peptidase-4 (DPP-4) inhibitors are accepted as a favorable class of agents for the treatment of type 2 diabetes. Herein, a series of fused β-homophenylalanine derivatives as novel DPP-4 inhibitors were designed, synthesized, and evaluated for their inhibitory activities against DPP-4. Most of them displayed excellent DPP-4 inhibitory activities and good selectivity. Among them, 9aa, 18a, and 18m also showed good efficacy in an oral glucose tolerance test (OGTT) in ICR mice. Moreover, when dosed 8 h prior to glucose challenge, 18m showed significantly greater potency than sitagliptin. It thus provides potential candidates for the further development into potent drugs targeting DPP-4.
|
Anti-diabetic effect in ICR mouse assessed as plasma glucose lowering effect at 10 mg/kg, po treated 1 hr before 2.5 mg/kg, po glucose load measured after 8 hrs by Oral glucose tolerance test relative to control
|
Mus musculus
|
24.0
%
|
|
Journal : ACS Med. Chem. Lett.
Title : Design, Synthesis, and Pharmacological Evaluation of Fused β-Homophenylalanine Derivatives as Potent DPP-4 Inhibitors.
Year : 2015
Volume : 6
Issue : 5
First Page : 602
Last Page : 606
Authors : Jiang T, Zhou Y, Chen Z, Sun P, Zhu J, Zhang Q, Wang Z, Shao Q, Jiang X, Li B, Chen K, Jiang H, Wang H, Zhu W, Shen J.
Abstract : Dipeptidyl peptidase-4 (DPP-4) inhibitors are accepted as a favorable class of agents for the treatment of type 2 diabetes. Herein, a series of fused β-homophenylalanine derivatives as novel DPP-4 inhibitors were designed, synthesized, and evaluated for their inhibitory activities against DPP-4. Most of them displayed excellent DPP-4 inhibitory activities and good selectivity. Among them, 9aa, 18a, and 18m also showed good efficacy in an oral glucose tolerance test (OGTT) in ICR mice. Moreover, when dosed 8 h prior to glucose challenge, 18m showed significantly greater potency than sitagliptin. It thus provides potential candidates for the further development into potent drugs targeting DPP-4.
|
Inhibition of human DPP4
|
Homo sapiens
|
12.0
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 recombinant DPP-4 using Gly-pro-p-nitroanilide as substrate assessed as formation of p-nitroaniline after 30 mins by colorimetric assay
|
Homo sapiens
|
18.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and biological evaluation of novel pyrazolo-pyrimidinones as DPP-IV inhibitors in diabetes.
Year : 2015
Volume : 25
Issue : 20
First Page : 4428
Last Page : 4433
Authors : Sagar SR, Agarwal JK, Pandya DH, Dash RP, Nivsarkar M, Vasu KK.
Abstract : We report the design, synthesis, biological activity and docking studies of series of novel pyrazolo[3,4-d]pyrimidinones as DPP-IV inhibitors in diabetes. Molecules were synthesized and evaluated for their DPP-IV inhibition activity. Compounds 5e, 5k, 5o and 6a were found to be potent inhibitors of DPP-IV enzyme. Amongst all the synthesized compounds, 6-methyl-5-(4-methylpyridin-2-yl)-1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4(5H)-one (5k) was found to be the most active based on in vitro DPP-IV studies and also exhibited promising in vivo blood glucose lowering activity in male Wistar rats.
|
Inhibition of DPP-4 (unknown origin)
|
Homo sapiens
|
18.0
nM
|
|
Journal : J. Med. Chem.
Title : Applications of Fluorine in Medicinal Chemistry.
Year : 2015
Volume : 58
Issue : 21
First Page : 8315
Last Page : 8359
Authors : Gillis EP, Eastman KJ, Hill MD, Donnelly DJ, Meanwell NA.
Abstract : The role of fluorine in drug design and development is expanding rapidly as we learn more about the unique properties associated with this unusual element and how to deploy it with greater sophistication. The judicious introduction of fluorine into a molecule can productively influence conformation, pKa, intrinsic potency, membrane permeability, metabolic pathways, and pharmacokinetic properties. In addition, (18)F has been established as a useful positron emitting isotope for use with in vivo imaging technology that potentially has extensive application in drug discovery and development, often limited only by convenient synthetic accessibility to labeled compounds. The wide ranging applications of fluorine in drug design are providing a strong stimulus for the development of new synthetic methodologies that allow more facile access to a wide range of fluorinated compounds. In this review, we provide an update on the effects of the strategic incorporation of fluorine in drug molecules and applications in positron emission tomography.
|
Inhibition of DPP4 (unknown origin) expressed in Sf9 cells using Gly-Pro-AMC substrate
|
Homo sapiens
|
6.24
nM
|
|
Journal : J Med Chem
Title : Discovery and Rational Design of Natural-Product-Derived 2-Phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes.
Year : 2016
Volume : 59
Issue : 14
First Page : 6772
Last Page : 6790
Authors : Li S, Xu H, Cui S, Wu F, Zhang Y, Su M, Gong Y, Qiu S, Jiao Q, Qin C, Shan J, Zhang M, Wang J, Yin Q, Xu M, Liu X, Wang R, Zhu L, Li J, Xu Y, Jiang H, Zhao Z, Li J, Li H.
Abstract : Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 ≈ 2.0 nM) with good pharmacokinetic profiles. Compound 22a demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of 22a in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented.
|
Binding affinity to DPP4 (unknown origin) assessed as dissociation constant by SPR assay
|
Homo sapiens
|
12.7
nM
|
|
Journal : J Med Chem
Title : Discovery and Rational Design of Natural-Product-Derived 2-Phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine Analogs as Novel and Potent Dipeptidyl Peptidase 4 (DPP-4) Inhibitors for the Treatment of Type 2 Diabetes.
Year : 2016
Volume : 59
Issue : 14
First Page : 6772
Last Page : 6790
Authors : Li S, Xu H, Cui S, Wu F, Zhang Y, Su M, Gong Y, Qiu S, Jiao Q, Qin C, Shan J, Zhang M, Wang J, Yin Q, Xu M, Liu X, Wang R, Zhu L, Li J, Xu Y, Jiang H, Zhao Z, Li J, Li H.
Abstract : Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 ≈ 2.0 nM) with good pharmacokinetic profiles. Compound 22a demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of 22a in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented.
|
Inhibition of DPP4 (unknown origin) using Gly-Pro-p-nitroanilide as substrate at 10 uM incubated for 1 hr
|
Homo sapiens
|
99.0
%
|
|
Journal : Eur J Med Chem
Title : Discovery of novel xanthine compounds targeting DPP-IV and GPR119 as anti-diabetic agents.
Year : 2016
Volume : 124
First Page : 103
Last Page : 116
Authors : Li G, Huan Y, Yuan B, Wang J, Jiang Q, Lin Z, Shen Z, Huang H.
Abstract : A series of xanthine derivatives as potent dual ligands targeting DPP-IV and GPR119 was discovered through an approach of the merged pharmacophores of GPR119 agonists and DPP-IV inhibitor linagliptin. Systematic optimization of general structure 5 led to the identification of compound 20i with selective DPP-IV inhibition, good GPR119 agonism activity and favorable metabolic stability. Docking study was performed to elucidate the potent DPP-IV inhibition of 20i. Compound 20i may serve as a tool compound for further design of anti-diabetic drugs targeting both DPP-IV and GPR119.
|
Inhibition of DPP4 (unknown origin) using Gly-Pro-p-nitroanilide as substrate incubated for 1 hr
|
Homo sapiens
|
17.0
nM
|
|
Journal : Eur J Med Chem
Title : Discovery of novel xanthine compounds targeting DPP-IV and GPR119 as anti-diabetic agents.
Year : 2016
Volume : 124
First Page : 103
Last Page : 116
Authors : Li G, Huan Y, Yuan B, Wang J, Jiang Q, Lin Z, Shen Z, Huang H.
Abstract : A series of xanthine derivatives as potent dual ligands targeting DPP-IV and GPR119 was discovered through an approach of the merged pharmacophores of GPR119 agonists and DPP-IV inhibitor linagliptin. Systematic optimization of general structure 5 led to the identification of compound 20i with selective DPP-IV inhibition, good GPR119 agonism activity and favorable metabolic stability. Docking study was performed to elucidate the potent DPP-IV inhibition of 20i. Compound 20i may serve as a tool compound for further design of anti-diabetic drugs targeting both DPP-IV and GPR119.
|
Inhibition of Wistar rat plasma DPP4
|
Rattus norvegicus
|
33.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Approaches towards the development of chimeric DPP4/ACE inhibitors for treating metabolic syndrome.
Year : 2017
Volume : 27
Issue : 11
First Page : 2313
Last Page : 2318
Authors : Sattigeri JA, Sethi S, Davis JA, Ahmed S, Rayasam GV, Jadhav BG, Chilla SM, Datta D, Gadhave A, Tulasi VK, Jain T, Voleti S, Benjamin B, Udupa S, Jain G, Singh Y, Srinivas K, Bansal VS, Ray A, Bhatnagar PK, Cliffe IA.
Abstract : Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.
|
Inhibition of ob/ob mouse plasma DPP4
|
Mus musculus
|
46.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Approaches towards the development of chimeric DPP4/ACE inhibitors for treating metabolic syndrome.
Year : 2017
Volume : 27
Issue : 11
First Page : 2313
Last Page : 2318
Authors : Sattigeri JA, Sethi S, Davis JA, Ahmed S, Rayasam GV, Jadhav BG, Chilla SM, Datta D, Gadhave A, Tulasi VK, Jain T, Voleti S, Benjamin B, Udupa S, Jain G, Singh Y, Srinivas K, Bansal VS, Ray A, Bhatnagar PK, Cliffe IA.
Abstract : Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.
|
Inhibition of human plasma DPP4
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Approaches towards the development of chimeric DPP4/ACE inhibitors for treating metabolic syndrome.
Year : 2017
Volume : 27
Issue : 11
First Page : 2313
Last Page : 2318
Authors : Sattigeri JA, Sethi S, Davis JA, Ahmed S, Rayasam GV, Jadhav BG, Chilla SM, Datta D, Gadhave A, Tulasi VK, Jain T, Voleti S, Benjamin B, Udupa S, Jain G, Singh Y, Srinivas K, Bansal VS, Ray A, Bhatnagar PK, Cliffe IA.
Abstract : Designing drug candidates exhibiting polypharmacology is one of the strategies adopted by medicinal chemists to address multifactorial diseases. Metabolic disease is one such multifactorial disorder characterized by hyperglycaemia, hypertension and dyslipidaemia among others. In this paper we report a new class of molecular framework combining the pharmacophoric features of DPP4 inhibitors with those of ACE inhibitors to afford potent dual inhibitors of DPP4 and ACE.
|
Inhibition of human recombinant C-terminal 6His-tagged DPP-4 expressed in insect cells incubated for 30 mins by TPE-KFPE fluorescent probe-based assay
|
Homo sapiens
|
37.96
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors.
Year : 2018
Volume : 28
Issue : 12
First Page : 2131
Last Page : 2135
Authors : Li N, Wang LJ, Jiang B, Guo SJ, Li XQ, Chen XC, Luo J, Li C, Wang Y, Shi DY.
Abstract : A series of novel pyrimidinedione derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) inhibitory activity and in vivo anti-hyperglycemic efficacy. Among them, the representative compounds 11, 15 and 16 showed excellent inhibitory activity of DPP-4 with IC50 values of 64.47 nM, 188.7 nM and 65.36 nM, respectively. Further studies revealed that compound 11 was potent in vivo hypoglycemic effect. The structure-activity relationships of these pyrimidinedione derivatives had been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes.
|
Inhibition of human recombinant C-terminal 6His-tagged DPP-4 expressed in insect cells at 100 nM to 10 uM incubated for 30 mins by TPE-KFPE fluorescent probe-based assay
|
Homo sapiens
|
100.49
%
|
|
Journal : Bioorg Med Chem Lett
Title : Design, synthesis and biological evaluation of novel pyrimidinedione derivatives as DPP-4 inhibitors.
Year : 2018
Volume : 28
Issue : 12
First Page : 2131
Last Page : 2135
Authors : Li N, Wang LJ, Jiang B, Guo SJ, Li XQ, Chen XC, Luo J, Li C, Wang Y, Shi DY.
Abstract : A series of novel pyrimidinedione derivatives were designed and evaluated for in vitro dipeptidyl peptidase-4 (DPP-4) inhibitory activity and in vivo anti-hyperglycemic efficacy. Among them, the representative compounds 11, 15 and 16 showed excellent inhibitory activity of DPP-4 with IC50 values of 64.47 nM, 188.7 nM and 65.36 nM, respectively. Further studies revealed that compound 11 was potent in vivo hypoglycemic effect. The structure-activity relationships of these pyrimidinedione derivatives had been discussed, which would be useful for developing novel DPP-4 inhibitors as treating type 2 diabetes.
|
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
|
40.0
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.
|
Inhibition of recombinant human DPP4 using Gly-Pro-AMC as substrate after 1 hr by fluorescence assay
|
Homo sapiens
|
7.8
nM
|
|
Journal : Eur J Med Chem
Title : Recent progress of the development of dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus.
Year : 2018
Volume : 151
First Page : 145
Last Page : 157
Authors : Li N, Wang LJ, Jiang B, Li XQ, Guo CL, Guo SJ, Shi DY.
Abstract : Diabetes is a fast growing chronic metabolic disorder around the world. Dipeptidyl peptidase-4 (DPP-4) is a new promising target during type 2 diabetes glycemic control. Thus, a number of potent DPP-4 inhibitors were developed and play a rapidly evolving role in the management of type 2 diabetes in recent years. This article reviews the development of synthetic and natural DPP-4 inhibitors from 2012 to 2017 and provides their physico-chemical properties, biological activities against DPP-4 and selectivity over dipeptidyl peptidase-8/9. Moreover, the glucose-lowering mechanisms and the active site of DPP-4 are also discussed. We also discuss strategies and structure-activity relationships for identifying potent DPP-4 inhibitors, which will provide useful information for developing potent DPP-4 drugs as type 2 diabtes treatments.
|
Inhibition of human DPP-4 using Ala-Pro-AMC as substrate preincubated for 10 mins followed by substrate addition and measured after 5 to 10 mins by fluorescence assay
|
Homo sapiens
|
120.0
nM
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis, nitric oxide release, and dipeptidyl peptidase-4 inhibition of sitagliptin derivatives as new multifunctional antidiabetic agents.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3731
Last Page : 3735
Authors : Xie Y, Shao L, Wang Q, Bai Y, Chen Z, Li N, Xu Y, Li Y, Yang G, Bian X.
Abstract : Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP-IV) in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds T1-T4 shown different extents of NO-releasing abilities and potent antioxidant abilities in vivo. By screening in DPP-4, compound T4 was recognized as a potent DPP-4 inhibitor with the IC<sub>50</sub> value of 0.060 μM. Docking study revealed compound T4 has a favorable binding mode. Furthermore, compounds T1-T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation in vitro. The overall results suggested that T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties.
|
Inhibition of ADP-induced platelet aggregation in human platelet-rich plasma at 0.1 mM preincubated for 5 mins followed by ADP-stimulation and measured within 5 mins by Born's turbidimetric analysis relative to control
|
Homo sapiens
|
4.24
%
|
|
Journal : Bioorg Med Chem Lett
Title : Synthesis, nitric oxide release, and dipeptidyl peptidase-4 inhibition of sitagliptin derivatives as new multifunctional antidiabetic agents.
Year : 2018
Volume : 28
Issue : 23-24
First Page : 3731
Last Page : 3735
Authors : Xie Y, Shao L, Wang Q, Bai Y, Chen Z, Li N, Xu Y, Li Y, Yang G, Bian X.
Abstract : Nitric oxide (NO) dysfunction has been found to be an important factor in both the development and progression of diabetic complications due to its many roles in the vascular system. Multifunctional compounds with hypoglycemic and endothelial protective action will be promising agents for the treatment of diabetes and its complications. In this study, a series of novel NO-donating sitagliptin derivatives and relevant metabolites were synthesized and evaluated as potential multifunctional hypoglycemic agents. All of synthetic compounds shown remarkable inhibitory activity against dipeptidyl peptidase IV (DPP-IV) in vitro and demonstrated excellent hypoglycemic activities in diabetic mice, similar to the activity of sitagliptin, and compounds T1-T4 shown different extents of NO-releasing abilities and potent antioxidant abilities in vivo. By screening in DPP-4, compound T4 was recognized as a potent DPP-4 inhibitor with the IC<sub>50</sub> value of 0.060 μM. Docking study revealed compound T4 has a favorable binding mode. Furthermore, compounds T1-T4 exhibited different extents of NO-releasing abilities and excellent anti-platelet aggregation in vitro. The overall results suggested that T4 could help to the amelioration of endothelial dysfunction by reducing blood glucose, lessening oxidative stress and raising NO levels as well as inhibiting platelet aggregation. Based on this research, compound T4 deserves further investigation as potential new multifunctional anti-diabetic agent with antioxidant, anti-platelet aggregation and endothelial protective properties.
|
Inhibition of DPP4 in C57BL/6 mouse serum pre-incubated for 5 mins followed by Gly-Pro-7-AMC substrate addition by fluorescence based assay
|
Mus musculus
|
14.7
nM
|
|
Journal : J Med Chem
Title : Discovery of Highly Polar β-Homophenylalanine Derivatives as Nonsystemic Intestine-Targeted Dipeptidyl Peptidase IV Inhibitors.
Year : 2019
Volume : 62
Issue : 23
First Page : 10919
Last Page : 10925
Authors : Huang F, Ning M, Wang K, Liu J, Guan W, Leng Y, Shen J.
Abstract : Although intensively expressed within intestine, the precise roles of intestinal dipeptidyl peptidase IV (DPPIV) in numerous pathologies remain incompletely understood. Here, we first reported a nonsystemic intestine-targeted (NSIT) DPPIV inhibitor with β-homophenylalanine scaffold, compound <b>7</b>, which selectively inhibited the intestinal rather than plasmatic DPPIV at an oral dosage as high as 30 mg/kg. We expect that compound <b>7</b> could serve as a qualified tissue-selective tool to determine undetected physiological or pathological roles of intestinal DPPIV.
|
Inhibition of recombinant human DPP4 expressed in baculovirus infected Sf9 insect cells at 200 nM using Gly-Pro-AMC as substrate measured at 60 secs interval for 20 mins by fluorescence assay relative to control
|
Homo sapiens
|
82.7
%
|
|
Journal : Bioorg Med Chem
Title : Identification of novel uracil derivatives incorporating benzoic acid moieties as highly potent Dipeptidyl Peptidase-IV inhibitors.
Year : 2019
Volume : 27
Issue : 4
First Page : 644
Last Page : 654
Authors : Huang J, Deng X, Zhou S, Wang N, Qin Y, Meng L, Li G, Xiong Y, Fan Y, Guo L, Lan D, Xing J, Jiang W, Li Q.
Abstract : Dipeptidyl Peptidase-IV (DPP-4) is a validated therapeutic target for type 2 diabetes. Aiming to interact with both residues Try629 and Lys554 in S<sub>2</sub>' site, a series of novel uracil derivatives 1a-l and 2a-i incorporating benzoic acid moieties at the N<sub>3</sub> position were designed and evaluated for their DPP-4 inhibitory activity. Structure-activity relationships (SAR) study led to the identification of the optimal compound 2b as a potent and selective DPP-4 inhibitor (IC<sub>50</sub> = 1.7 nM). Docking study revealed the additional salt bridge formed between the carboxylic acid and primary amine of Lys554 has a key role in the enhancement of the activity. Furthermore, compound 2b exhibited no cytotoxicity in human hepatocyte LO2 cells up to 50 μM. Subsequent in vivo evaluations revealed that the ester of 2b robustly improves the glucose tolerance in normal mice. The overall results have shown that compound 2b has the potential to a safe and efficacious treatment for T2DM.
|
Inhibition of recombinant human DPP4 expressed in baculovirus infected Sf9 insect cells at 40 nM using Gly-Pro-AMC as substrate measured at 60 secs interval for 20 mins by fluorescence assay relative to control
|
Homo sapiens
|
73.5
%
|
|
Journal : Bioorg Med Chem
Title : Identification of novel uracil derivatives incorporating benzoic acid moieties as highly potent Dipeptidyl Peptidase-IV inhibitors.
Year : 2019
Volume : 27
Issue : 4
First Page : 644
Last Page : 654
Authors : Huang J, Deng X, Zhou S, Wang N, Qin Y, Meng L, Li G, Xiong Y, Fan Y, Guo L, Lan D, Xing J, Jiang W, Li Q.
Abstract : Dipeptidyl Peptidase-IV (DPP-4) is a validated therapeutic target for type 2 diabetes. Aiming to interact with both residues Try629 and Lys554 in S<sub>2</sub>' site, a series of novel uracil derivatives 1a-l and 2a-i incorporating benzoic acid moieties at the N<sub>3</sub> position were designed and evaluated for their DPP-4 inhibitory activity. Structure-activity relationships (SAR) study led to the identification of the optimal compound 2b as a potent and selective DPP-4 inhibitor (IC<sub>50</sub> = 1.7 nM). Docking study revealed the additional salt bridge formed between the carboxylic acid and primary amine of Lys554 has a key role in the enhancement of the activity. Furthermore, compound 2b exhibited no cytotoxicity in human hepatocyte LO2 cells up to 50 μM. Subsequent in vivo evaluations revealed that the ester of 2b robustly improves the glucose tolerance in normal mice. The overall results have shown that compound 2b has the potential to a safe and efficacious treatment for T2DM.
|
Inhibition of recombinant human DPP4 expressed in baculovirus infected Sf9 insect cells using Gly-Pro-AMC as substrate measured at 60 secs interval for 20 mins by fluorescence assay
|
Homo sapiens
|
6.9
nM
|
|
Journal : Bioorg Med Chem
Title : Identification of novel uracil derivatives incorporating benzoic acid moieties as highly potent Dipeptidyl Peptidase-IV inhibitors.
Year : 2019
Volume : 27
Issue : 4
First Page : 644
Last Page : 654
Authors : Huang J, Deng X, Zhou S, Wang N, Qin Y, Meng L, Li G, Xiong Y, Fan Y, Guo L, Lan D, Xing J, Jiang W, Li Q.
Abstract : Dipeptidyl Peptidase-IV (DPP-4) is a validated therapeutic target for type 2 diabetes. Aiming to interact with both residues Try629 and Lys554 in S<sub>2</sub>' site, a series of novel uracil derivatives 1a-l and 2a-i incorporating benzoic acid moieties at the N<sub>3</sub> position were designed and evaluated for their DPP-4 inhibitory activity. Structure-activity relationships (SAR) study led to the identification of the optimal compound 2b as a potent and selective DPP-4 inhibitor (IC<sub>50</sub> = 1.7 nM). Docking study revealed the additional salt bridge formed between the carboxylic acid and primary amine of Lys554 has a key role in the enhancement of the activity. Furthermore, compound 2b exhibited no cytotoxicity in human hepatocyte LO2 cells up to 50 μM. Subsequent in vivo evaluations revealed that the ester of 2b robustly improves the glucose tolerance in normal mice. The overall results have shown that compound 2b has the potential to a safe and efficacious treatment for T2DM.
|
Binding affinity to human recombinant DPP4 (39 to 766 residues) by surface plasmon resonance analysis
|
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.
|
Binding affinity to human recombinant DPP4 (39 to 766 residues) at 5 uM by isothermal titration calorimetry
|
Homo sapiens
|
13.5
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 DPP4 (unknown origin) expressed in baculovirus expressing system
|
Homo sapiens
|
12.7
nM
|
|
Journal : J Med Chem
Title : Discovery of a Natural-Product-Derived Preclinical Candidate for Once-Weekly Treatment of Type 2 Diabetes.
Year : 2019
Volume : 62
Issue : 5
First Page : 2348
Last Page : 2361
Authors : Li S, Qin C, Cui S, Xu H, Wu F, Wang J, Su M, Fang X, Li D, Jiao Q, Zhang M, Xia C, Zhu L, Wang R, Li J, Jiang H, Zhao Z, Li J, Li H.
Abstract : Poor medication adherence is one of the leading causes of suboptimal glycaemic control in approximately half of the patients with type 2 diabetes mellitus (T2DM). Long-acting antidiabetic drugs are clinically needed for improving patients' compliance. Dipeptidyl peptidase-4 (DPP-4) inhibitors play an increasingly important role in the treatment of T2DM because of their favorable properties of weight neutrality and hypoglycemia avoidance. Herein, we report the successful discovery and scale-up synthesis of compound 5, a structurally novel, potent, and long-acting DPP-4 inhibitor for the once-weekly treatment of T2DM. Inhibitor 5 has fast-associating and slow-dissociating binding kinetics profiles as well as slow clearance rate and long terminal half-life pharmacokinetic properties. A single-dose oral administration of 5 (3 mg/kg) inhibited >80% of DPP-4 activity for more than 7 days in diabetic mice. The long-term antidiabetic efficacies of 5 (10 mg/kg, qw) were better than those of the once-weekly trelagliptin and omarigliptin, especially in decreasing the hemoglobin A1c level.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
6.08
%
|
|
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
|
-0.01
%
|
|
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
|
-0.01
%
|
|
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.
|
Inhibition of human SET7 overexpressed in Escherichia coli BL21 (DE3) cells at 25 uM preincubated for 15 mins followed by addition of SAM as substrate and biotinylated Histone H3 (1-50) peptide measured after 30 mins by AlphaLISA assay relative to control
|
Homo sapiens
|
6.0
%
|
|
Journal : Bioorg Med Chem
Title : Computational discovery and biological evaluation of novel inhibitors targeting histone-lysine N-methyltransferase SET7.
Year : 2020
Volume : 28
Issue : 7
First Page : 115372
Last Page : 115372
Authors : Min W, Hou Z, Zhang F, Xie S, Yuan K, Dong H, Wang L, Qi L, Luo C, Ding H, Yang P.
Abstract : Histone-lysine N-methyltransferase SET7 emerged as a potential target for multiple cancers. In a virtual screening program used to explore new and potent inhibitors of SET7, compound 16 was discovered as a top hit with an IC<sub>50</sub> value of 6.02 μM. A further similarity search afforded a new compound 23, which exhibited better activity against SET7 with an IC<sub>50</sub> value of 1.96 μM. Importantly, compound 23 selectively inhibited the proliferation of MV4-11 cells. Comprehensively, compound 23 can serve as a lead for further identification and development of more potent SET7 inhibitors.
|
Inhibition of DPP4 (unknown origin) at 10 uM using Gly-Pro-p-nitroanilide as substrate incubated for 1 hr relative to control
|
Homo sapiens
|
99.0
%
|
|
Journal : Eur J Med Chem
Title : The optimization of xanthine derivatives leading to HBK001 hydrochloride as a potent dual ligand targeting DPP-IV and GPR119.
Year : 2020
Volume : 188
First Page : 112017
Last Page : 112017
Authors : Li G,Meng B,Yuan B,Huan Y,Zhou T,Jiang Q,Lei L,Sheng L,Wang W,Gong N,Lu Y,Ma C,Li Y,Shen Z,Huang H
Abstract : A series of xanthine compounds derived from the previous hit 20i with modification on the terminal side chain was discovered through ring formation strategy. Systematic optimization of the compounds with rigid heterocycles in the hydrophobic side chain led to the new lead compound HBK001 (21h) with the improved DPP-IV inhibition and moderate GPR119 agonism activity in vitro. As a continuing work to further study the PK and PD profiles, 21h and its hydrochloride (22) were synthesized on grams scale and evaluated on the ADME/T and oral glucose tolerance test (OGTT) in ICR mice. Compound 22 showed the improved bioavailability and blood glucose-lowering effect in vivo compared to its free base 21h probably attributed to its improved solubility and permeability. The preliminary toxicity studies on compound 22 exhibited that the result of mini-Ames was negative and the preliminary acute toxicity LD in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC 4.9 μM maybe due to its high lipophilicity. These findings will be useful for the future drug design for more potent and safer dual ligand targeting DPP-IV and GPR119 for the treatment of diabetes.
|
Inhibition of DPP4 (unknown origin) using Gly-Pro-p-nitroanilide as substrate incubated for 1 hr
|
Homo sapiens
|
8.4
nM
|
|
Journal : Eur J Med Chem
Title : The optimization of xanthine derivatives leading to HBK001 hydrochloride as a potent dual ligand targeting DPP-IV and GPR119.
Year : 2020
Volume : 188
First Page : 112017
Last Page : 112017
Authors : Li G,Meng B,Yuan B,Huan Y,Zhou T,Jiang Q,Lei L,Sheng L,Wang W,Gong N,Lu Y,Ma C,Li Y,Shen Z,Huang H
Abstract : A series of xanthine compounds derived from the previous hit 20i with modification on the terminal side chain was discovered through ring formation strategy. Systematic optimization of the compounds with rigid heterocycles in the hydrophobic side chain led to the new lead compound HBK001 (21h) with the improved DPP-IV inhibition and moderate GPR119 agonism activity in vitro. As a continuing work to further study the PK and PD profiles, 21h and its hydrochloride (22) were synthesized on grams scale and evaluated on the ADME/T and oral glucose tolerance test (OGTT) in ICR mice. Compound 22 showed the improved bioavailability and blood glucose-lowering effect in vivo compared to its free base 21h probably attributed to its improved solubility and permeability. The preliminary toxicity studies on compound 22 exhibited that the result of mini-Ames was negative and the preliminary acute toxicity LD in mice was above 1.5 g/kg, while it showed moderate inhibition on hERG channel with IC 4.9 μM maybe due to its high lipophilicity. These findings will be useful for the future drug design for more potent and safer dual ligand targeting DPP-IV and GPR119 for the treatment of diabetes.
|
Inhibition of recombinant human DPP4 using Gly-Pro-AMC as substrate incubated for 1 hr by fluorogenic assay
|
Homo sapiens
|
7.8
nM
|
|
Journal : Bioorg Med Chem
Title : Synthesis, in vitro evaluation, and computational simulations studies of 1,2,3-triazole analogues as DPP-4 inhibitors.
Year : 2021
Volume : 29
First Page : 115861
Last Page : 115861
Authors : Vo DV,Hong KH,Lee J,Park H
Abstract : Novel 1,2,3-triazole analogues (S7 ~ S10) were synthesized and evaluated for their inhibitory activity against hDPP-4. All the 1,2,3-triazole analogues exhibited moderate in vitro hDPP-4 inhibitory activities (265 ~ 780 nM). These results are somewhat less potent compared to those of known 1,2,3-triazole analogues (S1 ~ S6, 14 ~ 254 nM). S2 and S3 manifested excellent potency against hDPP-4 with ICs of 28 and 14 nM, respectively. The role of the 1,2,3-triazole moiety in binding the molecule to the target was investigated using combined 10 1,2,3-triazole analogues (S1 ~ S10). Molecular dynamics (MD) simulations following the aforementioned docking phase were performed to elucidate potential binding modes of sitagliptin's 1,2,3-triazole analogues in hDPP-4, with the use of a cocrystal structure of hDPP-4 with sitagliptin (PDB ID: 1X70). Docking and MD simulations of the complexes of hDPP-4 with sitagliptin, S2 and S3 suggest that Glu205, Glu206, Tyr662, and Tyr666 would be the key amino acid residues for the binding of the molecules with the receptor. Especially, S2 and S3 showed additional strong π-π interaction between Phe357 and 1,2,3-triazole. Same strong π-π interaction is also observed between Phe357 and the 1,2,4-triazole ring of sitagliptin. Furthermore, additional interactions with Tyr547, Cys551, and especially Arg358 would enhance the binding affinity of the compounds for the pocket of the enzyme. In overall, in vitro hDPP-4 inhibitory activities of synthetic 1,2,3-triazole analogues were well matched with results of computational simulations studies.
