|
Inhibitory activity against dipeptidylpeptidase IV.
|
None
|
34.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : 4-Amino cyclohexylglycine analogues as potent dipeptidyl peptidase IV inhibitors.
Year : 2004
Volume : 14
Issue : 1
First Page : 43
Last Page : 46
Authors : Parmee ER, He J, Mastracchio A, Edmondson SD, Colwell L, Eiermann G, Feeney WP, Habulihaz B, He H, Kilburn R, Leiting B, Lyons K, Marsilio F, Patel RA, Petrov A, Di Salvo J, Wu JK, Thornberry NA, Weber AE.
Abstract : Substituted 4-amino cyclohexylglycine analogues were evaluated for DP-IV inhibitory properties. Bis-sulfonamide 15e was an extremely potent 2.6 nM inhibitor of the enzyme with excellent selectivity over all counterscreens. 2,4-difluorobenzenesulfonamide 15b and 1-naphthyl amide 16b, however, combined an acceptable in vitro profile with good pharmacokinetic properties in the rat, and 15b was orally efficacious at 3 mpk in an OGTT in lean mice.
|
Inhibitory concentration against Dipeptidylpeptidase IV [DPP-IV]
|
None
|
51.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Glutamic acid analogues as potent dipeptidyl peptidase IV and 8 inhibitors.
Year : 2005
Volume : 15
Issue : 13
First Page : 3271
Last Page : 3275
Authors : Lu IL, Lee SJ, Tsu H, Wu SY, Kao KH, Chien CH, Chang YY, Chen YS, Cheng JH, Chang CN, Chen TW, Chang SP, Chen X, Jiaang WT.
Abstract : To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine with P2-site 4-substituted glutamic acid derivatives and tested their activities against DPP-IV, DPP8, and DPP-II. Analogues that incorporated a bulky substituent at the first carbon position of benzylamine or isoquinoline showed over 30-fold selectivity for DPP-IV over both DPP8 and DPP-II. From structure-activity relationship studies, we speculate that the S2 site of DPP8 might be similar to that of DPP-IV, while DPP-IV inhibitor with N-substituted glycine in the P2 site and/or with a moiety involving in hydrophobic interaction with the side chain of Phe357 might provide a better selectivity for DPP-IV over DPP8.
|
Inhibitory concentration against dipeptidylpeptidase IV
|
None
|
3.5
nM
|
|
Journal : J. Med. Chem.
Title : Dipeptidyl peptidase IV inhibitors for the treatment of diabetes.
Year : 2004
Volume : 47
Issue : 17
First Page : 4135
Last Page : 4141
Authors : Weber AE.
|
Inhibitory concentration against dipeptidylpeptidase IV
|
None
|
51.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Novel isoindoline compounds for potent and selective inhibition of prolyl dipeptidase DPP8.
Year : 2005
Volume : 15
Issue : 3
First Page : 687
Last Page : 691
Authors : Jiaang WT, Chen YS, Hsu T, Wu SH, Chien CH, Chang CN, Chang SP, Lee SJ, Chen X.
Abstract : DPP8 is a prolyl dipeptidase homologous to DPP-IV, which is a drug target for Type II diabetes. The biological function of DPP8 is not known. To identify potent and selective chemical compounds against DPP8, we have synthesized a series of isoquinoline and isoindoline derivatives and have tested their inhibitory activity against DPP8, DPP-IV and DPP-II. Isoindoline derivatives were found to be more potent DPP8 inhibitors than isoquinoline derivatives. Isoindoline with a 1-(4,4'-difluor-benzhydryl)-piperazine group at the P2 site was observed to be a very potent DPP8 inhibitor, having an IC(50) value of 14nM with at least a 2500-fold selectivity over either DPP-IV or DPP-II. From SAR results, we speculate that the S1 site of DPP8 may be larger than that of DPP-IV, which would allow the accommodation of larger C-terminal residues, such as isoquinoline or isoindoline.
|
Inhibitory activity against DPP4
|
Homo sapiens
|
51.0
nM
|
|
Journal : J. Med. Chem.
Title : 2-[3-[2-[(2S)-2-Cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]- 1,2,3,4-tetrahydroisoquinoline: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.
Year : 2006
Volume : 49
Issue : 1
First Page : 373
Last Page : 380
Authors : Tsu H, Chen X, Chen CT, Lee SJ, Chang CN, Kao KH, Coumar MS, Yeh YT, Chien CH, Wang HS, Lin KT, Chang YY, Wu SH, Chen YS, Lu IL, Wu SY, Tsai TY, Chen WC, Hsieh HP, Chao YS, Jiaang WT.
Abstract : Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC(50) values of <50 nM with excellent selectivity over both DPP8 (IC(50) > 100 microM) and DPP-II (IC(50) > 30 microM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development.
|
Inhibition of plasma DPP4 in BALB/c mice 30 min after administration of 18 mg/kg, po
|
Mus musculus
|
80.0
%
|
|
Journal : J. Med. Chem.
Title : 2-[3-[2-[(2S)-2-Cyano-1-pyrrolidinyl]-2-oxoethylamino]-3-methyl-1-oxobutyl]- 1,2,3,4-tetrahydroisoquinoline: a potent, selective, and orally bioavailable dipeptide-derived inhibitor of dipeptidyl peptidase IV.
Year : 2006
Volume : 49
Issue : 1
First Page : 373
Last Page : 380
Authors : Tsu H, Chen X, Chen CT, Lee SJ, Chang CN, Kao KH, Coumar MS, Yeh YT, Chien CH, Wang HS, Lin KT, Chang YY, Wu SH, Chen YS, Lu IL, Wu SY, Tsai TY, Chen WC, Hsieh HP, Chao YS, Jiaang WT.
Abstract : Dipeptidyl peptidase IV (DPP-IV) inhibitors are expected to become a new type of antidiabetic drugs. Most known DPP-IV inhibitors often resemble the dipeptide cleavage products, with a proline mimic at the P1 site. As off-target inhibitions of DPP8 and/or DPP9 have shown profound toxicities in the in vivo studies, it is important to develop selective DPP-IV inhibitors for clinical usage. To achieve this, a new class of 2-[3-[[2-[(2S)-2-cyano-1-pyrrolidinyl]-2-oxoethyl]amino]-1-oxopropyl]-based DPP-IV inhibitors was synthesized. SAR studies resulted in a number of DPP-IV inhibitors, having IC(50) values of <50 nM with excellent selectivity over both DPP8 (IC(50) > 100 microM) and DPP-II (IC(50) > 30 microM). Compound 21a suppressed the blood glucose elevation after an oral glucose challenge in Wistar rats and also inhibited plasma DPP-IV activity for up to 4 h in BALB/c mice. The results show that compound 21a possesses in vitro and in vivo activities comparable to those of NVP-LAF237 (4), which is in clinical development.
|
Inhibition of human DPP4 expressed in Caco-2 cells
|
Homo sapiens
|
4.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.
Year : 2006
Volume : 49
Issue : 21
First Page : 6416
Last Page : 6420
Authors : Madar DJ, Kopecka H, Pireh D, Yong H, Pei Z, Li X, Wiedeman PE, Djuric SW, Von Geldern TW, Fickes MG, Bhagavatula L, McDermott T, Wittenberger S, Richards SJ, Longenecker KL, Stewart KD, Lubben TH, Ballaron SJ, Stashko MA, Long MA, Wells H, Zinker BA, Mika AK, Beno DW, Kempf-Grote AJ, Polakowski J, Segreti J, Reinhart GA, Fryer RM, Sham HL, Trevillyan JM.
Abstract : Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
|
Inhibition of DPP9
|
Homo sapiens
|
68.0
nM
|
|
Journal : J. Med. Chem.
Title : Discovery of 2-[4-{{2-(2S,5R)-2-cyano-5-ethynyl-1-pyrrolidinyl]-2-oxoethyl]amino]- 4-methyl-1-piperidinyl]-4-pyridinecarboxylic acid (ABT-279): a very potent, selective, effective, and well-tolerated inhibitor of dipeptidyl peptidase-IV, useful for the treatment of diabetes.
Year : 2006
Volume : 49
Issue : 21
First Page : 6416
Last Page : 6420
Authors : Madar DJ, Kopecka H, Pireh D, Yong H, Pei Z, Li X, Wiedeman PE, Djuric SW, Von Geldern TW, Fickes MG, Bhagavatula L, McDermott T, Wittenberger S, Richards SJ, Longenecker KL, Stewart KD, Lubben TH, Ballaron SJ, Stashko MA, Long MA, Wells H, Zinker BA, Mika AK, Beno DW, Kempf-Grote AJ, Polakowski J, Segreti J, Reinhart GA, Fryer RM, Sham HL, Trevillyan JM.
Abstract : Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
|
Inhibition of DPP9
|
None
|
680.0
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 DPP4
|
None
|
120.0
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
|
Homo sapiens
|
51.0
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
|
34.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Medicinal chemistry approaches to the inhibition of dipeptidyl peptidase-4 for the treatment of type 2 diabetes.
Year : 2009
Volume : 17
Issue : 5
First Page : 1783
Last Page : 1802
Authors : Havale SH, Pal M.
Abstract : Emerging as an epidemic of the 21st century type 2 diabetes has become a major health problem throughout the globe. The number of deaths attributable to diabetes reflects the insufficient glycemic control achieved with the treatments used in recent past. DPP-4 inhibitors have been investigated as a new therapy with novel mechanisms of action and improved tolerability. DPP-4, a protease that specifically cleaves dipeptides from proteins and oligopeptides after a penultimate N-terminal proline or alanine, is involved in the degradation of a number of neuropeptides, peptide hormones and cytokines, including the incretins GLP-1 and GIP. As soon as released from the gut in response to food intake, GLP-1 and GIP exert a potent glucose-dependent insulinotropic action, thereby playing a key role in the maintenance of post-meal glycemic control. Consequently, inhibiting DPP-4 prolongs the action of GLP-1 and GIP, which in turn improves glucose homeostasis with a low risk of hypoglycemia and potential for disease modification. Indeed, clinical trials involving diabetic patients have shown improved glucose control by administering DPP-4 inhibitors, thus demonstrating the benefit of this promising new class of antidiabetics. Intense research activities in this area have resulted in the launch of sitagliptin and vildagliptin (in Europe only) and the advancement of a few others into preregistration/phase 3, for example, saxagliptin, alogliptin and ABT-279. Achieving desired selectivity for DPP-4 over other related peptidases such as DPP-8 and DPP-9 (inhibition of which was linked to toxicity in animal studies) and long-acting potential for maximal efficacy (particularly in more severe diabetic patients) were the major challenges. Whether these goals are achieved with the present series of inhibitors in the advanced stages of clinical development is yet to be confirmed. Nevertheless, treatment of this metabolic disorder especially in the early stages of the disease via DPP-4 inhibition has been recognized as a validated principle and a large number of inhibitors are presently in various stage of pre-clinical/clinical development. Sitagliptin is a new weapon in the arsenal of oral antihyperglycemic agents. This review will focus on the journey of drug discovery of DPP-4 inhibitors for oral delivery covering a brief scientific background and medicinal chemistry approaches along with the status of advanced clinical candidates.
|
Inhibition of DPP4
|
None
|
56.0
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 plasma DPP4 in Wistar rat at 3 mg/kg, po measured 30 mins to 4 hrs
|
Rattus norvegicus
|
80.0
%
|
|
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 plasma DPP4 in Wistar rat at 3 mg/kg, po measured after 8 hrs
|
Rattus norvegicus
|
60.0
%
|
|
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 human recombinant DPP4 by fluorescence assay
|
Homo sapiens
|
3.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Bicyclic cyanothiazolidines as novel dipeptidyl peptidase 4 inhibitors.
Year : 2009
Volume : 19
Issue : 15
First Page : 4437
Last Page : 4440
Authors : Betancort JM, Winn DT, Liu R, Xu Q, Liu J, Liao W, Chen SH, Carney D, Hanway D, Schmeits J, Li X, Gordon E, Campbell DA.
Abstract : The synthesis and biochemical evaluation of novel cyanothiazolidine inhibitors of dipeptidyl peptidase 4 (DPP4) is described. Their main structural feature is a constrained bicyclic core that prevents the intramolecular formation of inactive cyclic species. The inhibitors show good to moderate biochemical potency against DPP4 and display distinct selectivity profiles towards DPP7, DPP8 and DPP9 depending on their substitution.
|
Inhibition of human DPP4 by fluorimetry
|
Homo sapiens
|
16.6
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
|
3.5
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
|
51.0
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
|
84.0
%
|
|
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
|
73.0
%
|
|
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
|
17.0
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
|
16.0
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
|
None
|
9.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of azobicyclo[3.3.0] octane derivatives as dipeptidyl peptidase 4 inhibitors for the treatment of type 2 diabetes.
Year : 2010
Volume : 20
Issue : 12
First Page : 3565
Last Page : 3568
Authors : Cho TP, Long YF, Gang LZ, Yang W, Jun LH, Yuan SG, Hong FJ, Lin W, Liang GD, Lei Z, Jing LJ, Shen GA, Hong SG, Dan W, Ying F, Ke YP, Ying L, Jun F, Tai MX.
Abstract : A series of novel azobicyclo[3.3.0]octane derivatives were synthesized and evaluated as dipeptidyl peptidase 4 (DPP-4) inhibitors. The effort resulted in the discovery of inhibitor 2a, which exhibited excellent efficacies in an oral glucose tolerance test. Introduction of methyl group (2j) could prolong the inhibition of serum DPP-4 activity.
|
Inhibition of DPP9
|
None
|
230.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and biological evaluation of azobicyclo[3.3.0] octane derivatives as dipeptidyl peptidase 4 inhibitors for the treatment of type 2 diabetes.
Year : 2010
Volume : 20
Issue : 12
First Page : 3565
Last Page : 3568
Authors : Cho TP, Long YF, Gang LZ, Yang W, Jun LH, Yuan SG, Hong FJ, Lin W, Liang GD, Lei Z, Jing LJ, Shen GA, Hong SG, Dan W, Ying F, Ke YP, Ying L, Jun F, Tai MX.
Abstract : A series of novel azobicyclo[3.3.0]octane derivatives were synthesized and evaluated as dipeptidyl peptidase 4 (DPP-4) inhibitors. The effort resulted in the discovery of inhibitor 2a, which exhibited excellent efficacies in an oral glucose tolerance test. Introduction of methyl group (2j) could prolong the inhibition of serum DPP-4 activity.
|
Inhibition of human recombinant His-tagged DPP4 expressed in insect cells
|
Homo sapiens
|
56.0
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 DPP9
|
None
|
680.0
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
|
None
|
120.0
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
|
0.58
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
|
120.0
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 bovine testes DPP9 assessed as pNA release from Ala-Pro-p-nitroanilide substrate pre-incubated with enzyme for 15 min prior to substrate addition by fluorescence technique
|
Bos taurus
|
680.0
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 human DPP4 expressed in baculovirus expression system using Gly-Pro-AMC substrate incubated or 30 mins by fluorescence based assay
|
Homo sapiens
|
3.2
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Long-acting peptidomimetics based DPP-IV inhibitors.
Year : 2012
Volume : 22
Issue : 10
First Page : 3516
Last Page : 3521
Authors : Jadav P, Bahekar R, Shah SR, Patel D, Joharapurkar A, Kshirsagar S, Jain M, Shaikh M, Sairam KV.
Abstract : Pyrrolidine based peptidomimetics are reported as potent and selective DPP-IV inhibitors for the treatment of T2DM. Compounds 16c and 16d showed excellent in vitro potency and selectivity towards DPP-IV and the lead compound 16c showed sustained antihyperglycemic effects, along with improved pharmacokinetic profile.
|
Inhibition of DPP4 in human plasma using Gly-Pro-AMC as substrate by fluorimetric analysis
|
Homo sapiens
|
3.0
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 DPP9
|
None
|
95.0
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 DPP8
|
None
|
810.0
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
|
62.0
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
|
3.0
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.
|
Inhibition of human purified His-tagged DPP-9 assessed as cleavage of substrate using Gly-Pro-AMC chromogenic substrate after 60 mins by fluorescence spectrophotometry
|
Homo sapiens
|
66.0
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.
|
Inhibition of 6xHis-tagged recombinant DPP9 (unknown origin) expressed in baculovirus expression system assessed as hydrolysis of Ala-Pro-aminomethylcoumarin preincubated for 20 mins followed by Gly-PropNA3 Tos addition measured after 90 mins by fluorometric assay
|
Homo sapiens
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes.
Year : 2013
Volume : 21
Issue : 23
First Page : 7418
Last Page : 7429
Authors : Wang J, Feng Y, Ji X, Deng G, Leng Y, Liu H.
Abstract : A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC(50)=0.017 μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4=1324; DPP-9/DPP-4=1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague-Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent.
|
Inhibition of 6xHis-tagged recombinant human DPP4 expressed in baculovirus expression system assessed as hydrolysis of Ala-Pro-aminomethylcoumarin by fluorometric assay
|
Homo sapiens
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Synthesis and biological evaluation of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives as dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes.
Year : 2013
Volume : 21
Issue : 23
First Page : 7418
Last Page : 7429
Authors : Wang J, Feng Y, Ji X, Deng G, Leng Y, Liu H.
Abstract : A novel series of pyrrolidine-2-carbonitrile and 4-fluoropyrrolidine-2-carbonitrile derivatives was designed, synthesized, and found to act as dipeptidyl peptidase-4 (DPP-4) inhibitors. From this series of compounds, compound 17a was identified as an efficacious, safe, and selective inhibitor of DPP-4. In vivo studies in ICR and KKAy mice showed that administration of this compound resulted in decreased blood glucose in these mice after an oral glucose challenge. Compound 17a showed high DPP-4 inhibitory activity (IC(50)=0.017 μM), moderate selectivity against DPP-4 (selective ratio: DPP-8/DPP-4=1324; DPP-9/DPP-4=1164), and good efficacy in oral glucose tolerance tests in ICR and KKAy mice. These in vivo anti-diabetic properties and its desirable pharmacokinetic profile in Sprague-Dawley rats demonstrate that compound 17a is a promising candidate for development as an anti-diabetic agent.
|
Inhibition of DPP4 (unknown origin)
|
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
|
3.5
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 recombinant DPP4 expressed in baculovirus expression system using Ala-Pro-AMC as substrate by continuous fluorometric assay
|
Homo sapiens
|
70.0
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 DPP9 (unknown origin) expressed in baculovirus expression system using Ala-Pro-AMC as substrate by continuous fluorometric assay
|
Homo sapiens
|
200.0
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 human DPP4
|
Homo sapiens
|
23.0
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 DPP9 (unknown origin)
|
Homo sapiens
|
80.0
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 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 human DPP4
|
Homo sapiens
|
120.0
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 bovine DPP9
|
Bos taurus
|
680.0
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 Porphyromonas gingivalis N-terminal His-tagged DPP4 expressed in Escherichia coli using Gly-Pro-p-nitroanilide as substrate preincubated for 15 mins
|
Porphyromonas gingivalis
|
17.0
nM
|
|
Journal : Eur J Med Chem
Title : Crystal structure of Porphyromonas gingivalis dipeptidyl peptidase 4 and structure-activity relationships based on inhibitor profiling.
Year : 2017
Volume : 139
First Page : 482
Last Page : 491
Authors : Rea D, Van Elzen R, De Winter H, Van Goethem S, Landuyt B, Luyten W, Schoofs L, Van Der Veken P, Augustyns K, De Meester I, Fülöp V, Lambeir AM.
Abstract : The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P. gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biofilm formation and were more infective. The X-ray crystal structure of P. gingivalis DPP4 was solved at 2.2 Å resolution. Despite a sequence identity of 32%, the overall structure of the dimer was conserved between P. gingivalis DPP4 and mammalian orthologues. The structures of the substrate binding sites were also conserved, except for the region called S2-extensive, which is exploited by specific human DPP4 inhibitors currently used as antidiabetic drugs. Screening of a collection of 450 compounds as inhibitors revealed a structure-activity relationship that mimics in part that of mammalian DPP9. The functional similarity between human and bacterial DPP4 was confirmed using 124 potential peptide substrates.
|
Antiviral activity determined as inhibition of SARS-CoV-2 induced cytotoxicity of Caco-2 cells at 10 uM after 48 hours by high content imaging
|
Homo sapiens
|
-5.57
%
|
|
Title : Identification of inhibitors of SARS-CoV-2 in-vitro cellular toxicity in human (Caco-2) cells using a large scale drug repurposing collection
Year : 2020
Authors : Bernhard Ellinger, Denisa Bojkova, Andrea Zaliani, Jindrich Cinatl, Carsten Claussen, Sandra Westhaus, Jeanette Reinshagen, Maria Kuzikov, Markus Wolf, Gerd Geisslinger, Philip Gribbon, Sandra Ciesek
Abstract : To identify possible candidates for progression towards clinical studies against SARS-CoV-2, we screened a well-defined collection of 5632 compounds including 3488 compounds which have undergone clinical investigations (marketed drugs, phases 1 -3, and withdrawn) across 600 indications. Compounds were screened for their inhibition of viral induced cytotoxicity using the human epithelial colorectal adenocarcinoma cell line Caco-2 and a SARS-CoV-2 isolate. The primary screen of 5632 compounds gave 271 hits. A total of 64 compounds with IC50 <20 µM were identified, including 19 compounds with IC50 < 1 µM. Of this confirmed hit population, 90% have not yet been previously reported as active against SARS-CoV-2 in-vitro cell assays. Some 37 of the actives are launched drugs, 19 are in phases 1-3 and 10 pre-clinical. Several inhibitors were associated with modulation of host pathways including kinase signaling P53 activation, ubiquitin pathways and PDE activity modulation, with long chain acyl transferases were effective viral inhibitors.
|
Inhibition of DPP4 in human serum assessed as decrease in p-nitroaniline formation using Gly-Pro-p-nitroanilide as substrate at 100 uM preincubated for 5 mins followed by incubation with substrate for 15 mins by microplate reader analysis relative to control
|
Homo sapiens
|
94.66
%
|
|
Journal : Eur J Med Chem
Title : Nitrothiadiazolo[3,2-a]pyrimidines as promising antiglycating agents.
Year : 2020
Volume : 185
First Page : 111808
Last Page : 111808
Authors : Savateev K, Fedotov V, Butorin I, Eltsov O, Slepukhin P, Ulomsky E, Rusinov V, Litvinov R, Babkov D, Khokhlacheva E, Radaev P, Vassiliev P, Spasov A.
Abstract : Managing the advanced glycation end-products (AGEs) concentration is a reliable approach to achieve control over the pathogenesis of diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is also an attractive way to tackle type 2 diabetes mellitus (T2DM). We showed previously that azoloazine heterocycles have the potential to prevent the formation of AGEs and in this work, we conducted docking studies with DPP-4 of 5-alkylamino-6-nitro-1,3,4-thiadiazolo[3,2-a]pyrimidines. Consequently, we have developed a synthetic approach to these structures by chlorodeoxygenation and amination reactions. Antidiabetic properties of obtained compounds were studied by evaluating DPP-4 (ex vivo/in vitro) and AGEs formation inhibition (in vitro). It was shown that the nitrothiadiazolopyrimidines exhibit a higher antiglycation activity than reference compound aminoguanidine, but only moderate inhibition of DPP-4. The most active DPP-4 inhibitor 1l had IC50 of 55.87 μM and showed the ability to inhibit serum DPP-4 activity in rats after 10 mg/kg oral administration but with the less and shorter effect than vildagliptin. At the same time, 1l was the most active antiglycating compound in the series (IC50 134.4 μM). Copper chelation properties of synthesized compounds were also investigated since the formation of AGEs is catalyzed by the transition metal cations. A noticeable correlation between antiglycation activity and metal chelation was revealed. Both activities (antiglycation and copper chelation) correlated with quantum-chemical properties (calculated with ab initio) of the tested compounds. These findings will allow us to predict both activities in the future, without the need to model multiple steps of glycation reaction.
|
Inhibition of DPP4 in human serum assessed as decrease in p-nitroaniline formation using Gly-Pro-p-nitroanilide as substrate preincubated for 5 mins followed by incubation with substrate for 15 mins by microplate reader analysis
|
Homo sapiens
|
15.0
nM
|
|
Journal : Eur J Med Chem
Title : Nitrothiadiazolo[3,2-a]pyrimidines as promising antiglycating agents.
Year : 2020
Volume : 185
First Page : 111808
Last Page : 111808
Authors : Savateev K, Fedotov V, Butorin I, Eltsov O, Slepukhin P, Ulomsky E, Rusinov V, Litvinov R, Babkov D, Khokhlacheva E, Radaev P, Vassiliev P, Spasov A.
Abstract : Managing the advanced glycation end-products (AGEs) concentration is a reliable approach to achieve control over the pathogenesis of diabetic vascular complications. Inhibition of dipeptidyl peptidase-4 (DPP-4) is also an attractive way to tackle type 2 diabetes mellitus (T2DM). We showed previously that azoloazine heterocycles have the potential to prevent the formation of AGEs and in this work, we conducted docking studies with DPP-4 of 5-alkylamino-6-nitro-1,3,4-thiadiazolo[3,2-a]pyrimidines. Consequently, we have developed a synthetic approach to these structures by chlorodeoxygenation and amination reactions. Antidiabetic properties of obtained compounds were studied by evaluating DPP-4 (ex vivo/in vitro) and AGEs formation inhibition (in vitro). It was shown that the nitrothiadiazolopyrimidines exhibit a higher antiglycation activity than reference compound aminoguanidine, but only moderate inhibition of DPP-4. The most active DPP-4 inhibitor 1l had IC50 of 55.87 μM and showed the ability to inhibit serum DPP-4 activity in rats after 10 mg/kg oral administration but with the less and shorter effect than vildagliptin. At the same time, 1l was the most active antiglycating compound in the series (IC50 134.4 μM). Copper chelation properties of synthesized compounds were also investigated since the formation of AGEs is catalyzed by the transition metal cations. A noticeable correlation between antiglycation activity and metal chelation was revealed. Both activities (antiglycation and copper chelation) correlated with quantum-chemical properties (calculated with ab initio) of the tested compounds. These findings will allow us to predict both activities in the future, without the need to model multiple steps of glycation reaction.
|
Inhibition of DPP9 (unknown origin) using Gly-Pro-AMC as substrate preincubated for 15 mins followed by substrate addition measured at 60 secs interval for 20 mins by fluorometic method
|
Homo sapiens
|
50.0
nM
|
|
Journal : Eur J Med Chem
Title : Rapid generation of novel benzoic acid-based xanthine derivatives as highly potent, selective and long acting DPP-4 inhibitors: Scaffold-hopping and prodrug study.
Year : 2019
Volume : 180
First Page : 509
Last Page : 523
Authors : Li Q, Meng L, Zhou S, Deng X, Wang N, Ji Y, Peng Y, Xing J, Yao G.
Abstract : A series of novel xanthine derivatives 2a-l incorporating benzoic acid moieties were rapidly generated by using strategy of scaffold-hopping from our previously reported scaffold uracil to xanthine, a scaffold of approved drug linagliptin. After systematic structure-activity relationship (SAR) study around benzoic acid moieties, 5 novel DPP-4 inhibitors with low picomolar potency range (IC<sub>50</sub> < 1 nM) and excellent selectivity against various DPP-4 homologues were identified, in which the best one, compound 2f, with the IC<sub>50</sub> value of 0.1 nM for DPP-4, showed 22-fold improvement in inhibitory activity compared to lead compound uracil 1, its activity was 45-fold more potent than alogliptin. 2e, 2f, 2i and 2k were selected for pharmacokinetic evaluation, and 2f and 2i showed the better pharmacokinetic profiles after iv administration, but poor oral bioavailability. To improve the oral pharmacokinetic profile, prodrug design approach was performed around 2f and 2i. Esters of 2f and 2i were synthesized and evaluated for stability, toxicity and pharmacokinetics. Compound 3e, the methyl ester of compound 2f, was identified to demonstrate good stability, low toxicity and improved oral bioavailability, with 3-fold higher blood concentration compared to 2f in rats. The following in vivo evaluations revealed 3e provided a sustained pharmacodynamics effect for 48h, and robustly improved glucose tolerance in normal ICR and db/db mice in dose-dependent manner. Chronic treatments investigations demonstrated that 3e achieved more beneficial effects on fasting blood glucose levels and glucose tolerance than alogliptin in type 2 diabetic db/db mice. The overall results have shown that compound 3e has the potential to efficacious, safety and long-acting treatment for T2DM.
|
Inhibition of recombinant full-length human N-terminal GST-tagged DPP9 expressed in Sf9 insect cells using Gly-Pro-AMC as substrate measured at 60 secs interval for 20 mins by fluorescence assay
|
Homo sapiens
|
140.0
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.
|
Inhibition of human recombinant DPP4 (39 to 766 residues) using Ala-Pro-AFC as substrate incubated for 1 hr by fluorescence assay
|
Homo sapiens
|
95.0
nM
|
|
Journal : J Med Chem
Title : Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure.
Year : 2016
Volume : 59
Issue : 16
First Page : 7466
Last Page : 7477
Authors : Schnapp G, Klein T, Hoevels Y, Bakker RA, Nar H.
Abstract : The binding kinetics and thermodynamics of dipeptidyl peptidase (DPP)-4 inhibitors (gliptins) were investigated using surface plasmon resonance and isothermal titration calorimetry. Binding of gliptins to DPP-4 is a rapid electrostatically driven process. Off-rates were generally slow partly because of reversible covalent bond formation by some gliptins, and partly because of strong and extensive interactions. Binding of all gliptins is enthalpy-dominated due to strong ionic interactions and strong solvent-shielded hydrogen bonds. Using a congeneric series of molecules which represented the intermediates in the lead optimization program of linagliptin, the onset of slow binding kinetics and development of the thermodynamic repertoire were analyzed in the context of incremental changes of the chemical structures. All compounds rapidly associated, and therefore the optimization of affinity and residence time is highly correlated. The major contributor to the increasing free energy of binding was a strong increase of binding enthalpy, whereas entropic contributions remained low and constant despite significant addition of lipophilicity.
|
Binding affinity to human recombinant DPP4 (39 to 766 residues) by surface plasmon resonance analysis
|
Homo sapiens
|
2.4
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
|
10.7
nM
|
|
Journal : J Med Chem
Title : Comparative Analysis of Binding Kinetics and Thermodynamics of Dipeptidyl Peptidase-4 Inhibitors and Their Relationship to Structure.
Year : 2016
Volume : 59
Issue : 16
First Page : 7466
Last Page : 7477
Authors : Schnapp G, Klein T, Hoevels Y, Bakker RA, Nar H.
Abstract : The binding kinetics and thermodynamics of dipeptidyl peptidase (DPP)-4 inhibitors (gliptins) were investigated using surface plasmon resonance and isothermal titration calorimetry. Binding of gliptins to DPP-4 is a rapid electrostatically driven process. Off-rates were generally slow partly because of reversible covalent bond formation by some gliptins, and partly because of strong and extensive interactions. Binding of all gliptins is enthalpy-dominated due to strong ionic interactions and strong solvent-shielded hydrogen bonds. Using a congeneric series of molecules which represented the intermediates in the lead optimization program of linagliptin, the onset of slow binding kinetics and development of the thermodynamic repertoire were analyzed in the context of incremental changes of the chemical structures. All compounds rapidly associated, and therefore the optimization of affinity and residence time is highly correlated. The major contributor to the increasing free energy of binding was a strong increase of binding enthalpy, whereas entropic contributions remained low and constant despite significant addition of lipophilicity.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
15.01
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
-9.572
%
|
|
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
|
0.54
%
|
|
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
|
0.12
%
|
|
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
|
0.54
%
|
|
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
|
0.12
%
|
|
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 recombinant DPP9 using Gly-Pro-AMC as substrate preincubated for 15 mins followed by substrate addition and measured for 20 mins by fluorescence based microplate reader assay
|
Homo sapiens
|
0.12
nM
|
|
|
Inhibition of human recombinant DPP8 using Gly-Pro-AMC as substrate preincubated for 15 mins followed by substrate addition and measured for 20 mins by fluorescence based microplate reader assay
|
Homo sapiens
|
1.85
nM
|
|
