|
50% inhibition of human recombinant fibroblast collagenase (MMP-1, HFC)
|
None
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of Matrix Metalloproteinases: An examination of the S1 pocket
Year : 1997
Volume : 7
Issue : 2
First Page : 193
Last Page : 198
Authors : Miller A, Askew M, Beckett R, Bellamy CL, Bone EA, Coates RE, Davidson AH, Drummond AH, Huxley P, Martin FM, Saroglou L, Thompson AJ, van Dijk SE, Whittaker M
|
Compound concentration for 50% inhibition of human recombinant gelatinase A (MMP-2).
|
None
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of Matrix Metalloproteinases: An examination of the S1 pocket
Year : 1997
Volume : 7
Issue : 2
First Page : 193
Last Page : 198
Authors : Miller A, Askew M, Beckett R, Bellamy CL, Bone EA, Coates RE, Davidson AH, Drummond AH, Huxley P, Martin FM, Saroglou L, Thompson AJ, van Dijk SE, Whittaker M
|
50% inhibition of human recombinant stromelysin (MMP-3, HFS)
|
None
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of Matrix Metalloproteinases: An examination of the S1 pocket
Year : 1997
Volume : 7
Issue : 2
First Page : 193
Last Page : 198
Authors : Miller A, Askew M, Beckett R, Bellamy CL, Bone EA, Coates RE, Davidson AH, Drummond AH, Huxley P, Martin FM, Saroglou L, Thompson AJ, van Dijk SE, Whittaker M
|
Inhibition of matrix metalloprotease-1
|
Homo sapiens
|
1.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Picking the S1, S1' and S2' pockets of matrix metalloproteinases. A niche for potent acyclic sulfonamide inhibitors.
Year : 1999
Volume : 9
Issue : 12
First Page : 1691
Last Page : 1696
Authors : Hanessian S, Bouzbouz S, Boudon A, Tucker GC, Peyroulan D.
Abstract : A series of acyclic hydroxamic acids harboring strategically placed alpha-arylsulfonamido and thioether groups was synthesized and found to be potent inhibitors of various MMPs. An unprecedented cleavage of t-butyl hydroxamates to hydroxamic acids was found.
|
Inhibition of HFC MMP-1
|
None
|
5.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors.
Year : 1999
Volume : 9
Issue : 19
First Page : 2887
Last Page : 2892
Authors : Martin FM, Beckett RP, Bellamy CL, Courtney PF, Davies SJ, Drummond AH, Dodd R, Pratt LM, Patel SR, Ricketts ML, Todd RS, Tuffnell AR, Ward JW, Whittaker M.
Abstract : Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability.
|
Inhibition of matrix metalloprotease-13
|
Homo sapiens
|
3.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Picking the S1, S1' and S2' pockets of matrix metalloproteinases. A niche for potent acyclic sulfonamide inhibitors.
Year : 1999
Volume : 9
Issue : 12
First Page : 1691
Last Page : 1696
Authors : Hanessian S, Bouzbouz S, Boudon A, Tucker GC, Peyroulan D.
Abstract : A series of acyclic hydroxamic acids harboring strategically placed alpha-arylsulfonamido and thioether groups was synthesized and found to be potent inhibitors of various MMPs. An unprecedented cleavage of t-butyl hydroxamates to hydroxamic acids was found.
|
Inhibition of Coll-3 MMP-13
|
None
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors.
Year : 1999
Volume : 9
Issue : 19
First Page : 2887
Last Page : 2892
Authors : Martin FM, Beckett RP, Bellamy CL, Courtney PF, Davies SJ, Drummond AH, Dodd R, Pratt LM, Patel SR, Ricketts ML, Todd RS, Tuffnell AR, Ward JW, Whittaker M.
Abstract : Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability.
|
Inhibition of matrix metalloprotease-2
|
Homo sapiens
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Picking the S1, S1' and S2' pockets of matrix metalloproteinases. A niche for potent acyclic sulfonamide inhibitors.
Year : 1999
Volume : 9
Issue : 12
First Page : 1691
Last Page : 1696
Authors : Hanessian S, Bouzbouz S, Boudon A, Tucker GC, Peyroulan D.
Abstract : A series of acyclic hydroxamic acids harboring strategically placed alpha-arylsulfonamido and thioether groups was synthesized and found to be potent inhibitors of various MMPs. An unprecedented cleavage of t-butyl hydroxamates to hydroxamic acids was found.
|
Inhibition of Gel-A MMP-2
|
None
|
6.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors.
Year : 1999
Volume : 9
Issue : 19
First Page : 2887
Last Page : 2892
Authors : Martin FM, Beckett RP, Bellamy CL, Courtney PF, Davies SJ, Drummond AH, Dodd R, Pratt LM, Patel SR, Ricketts ML, Todd RS, Tuffnell AR, Ward JW, Whittaker M.
Abstract : Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability.
|
Inhibition of matrix metalloprotease-3
|
Homo sapiens
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Picking the S1, S1' and S2' pockets of matrix metalloproteinases. A niche for potent acyclic sulfonamide inhibitors.
Year : 1999
Volume : 9
Issue : 12
First Page : 1691
Last Page : 1696
Authors : Hanessian S, Bouzbouz S, Boudon A, Tucker GC, Peyroulan D.
Abstract : A series of acyclic hydroxamic acids harboring strategically placed alpha-arylsulfonamido and thioether groups was synthesized and found to be potent inhibitors of various MMPs. An unprecedented cleavage of t-butyl hydroxamates to hydroxamic acids was found.
|
Inhibition of Strom-1 MMP-3
|
None
|
200.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors.
Year : 1999
Volume : 9
Issue : 19
First Page : 2887
Last Page : 2892
Authors : Martin FM, Beckett RP, Bellamy CL, Courtney PF, Davies SJ, Drummond AH, Dodd R, Pratt LM, Patel SR, Ricketts ML, Todd RS, Tuffnell AR, Ward JW, Whittaker M.
Abstract : Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability.
|
Inhibition of HNC MMP-8
|
None
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis and biological evaluation of non-peptidic matrix metalloproteinase inhibitors.
Year : 1999
Volume : 9
Issue : 19
First Page : 2887
Last Page : 2892
Authors : Martin FM, Beckett RP, Bellamy CL, Courtney PF, Davies SJ, Drummond AH, Dodd R, Pratt LM, Patel SR, Ricketts ML, Todd RS, Tuffnell AR, Ward JW, Whittaker M.
Abstract : Novel sulfonamide matrix metalloproteinase inhibitors of general formula (9) were synthesised by a route involving a stereoselective conjugate addition reaction. Enzyme selectivity was found to be dependant on the nature of the sulfonamide substituents. Compounds (9f, 9q) are potent selective collagenase inhibitors with good oral bioavailability.
|
Inhibition of matrix metalloprotease-9
|
Homo sapiens
|
1.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Picking the S1, S1' and S2' pockets of matrix metalloproteinases. A niche for potent acyclic sulfonamide inhibitors.
Year : 1999
Volume : 9
Issue : 12
First Page : 1691
Last Page : 1696
Authors : Hanessian S, Bouzbouz S, Boudon A, Tucker GC, Peyroulan D.
Abstract : A series of acyclic hydroxamic acids harboring strategically placed alpha-arylsulfonamido and thioether groups was synthesized and found to be potent inhibitors of various MMPs. An unprecedented cleavage of t-butyl hydroxamates to hydroxamic acids was found.
|
In vitro inhibitory activity against matrix metalloprotease 1 isolated from the culture medium of human skin fibroblasts induced with PMA
|
None
|
1.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors.
Year : 1998
Volume : 8
Issue : 22
First Page : 3251
Last Page : 3256
Authors : Sheppard GS, Florjancic AS, Giesler JR, Xu L, Guo Y, Davidsen SK, Marcotte PA, Elmore I, Albert DH, Magoc TJ, Bouska JJ, Goodfellow CL, Morgan DW, Summers JB.
Abstract : A series of succinyl hydroxamate MMP inhibitors were prepared incorporating an aryl amino ketone moiety in place of the more typical C-terminal amino acid amides. Compounds of the C-terminal ketone series displayed potent inhibition of MMPs. Several compounds of the series were shown to be orally bioavailable.
|
In vitro inhibitory activity against matrix metalloprotease 2 isolated from human HT1080 fibrosarcoma cells induced with TNF
|
None
|
0.85
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors.
Year : 1998
Volume : 8
Issue : 22
First Page : 3251
Last Page : 3256
Authors : Sheppard GS, Florjancic AS, Giesler JR, Xu L, Guo Y, Davidsen SK, Marcotte PA, Elmore I, Albert DH, Magoc TJ, Bouska JJ, Goodfellow CL, Morgan DW, Summers JB.
Abstract : A series of succinyl hydroxamate MMP inhibitors were prepared incorporating an aryl amino ketone moiety in place of the more typical C-terminal amino acid amides. Compounds of the C-terminal ketone series displayed potent inhibition of MMPs. Several compounds of the series were shown to be orally bioavailable.
|
In vitro inhibitory activity against human recombinant matrix metalloprotease 3
|
None
|
10.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors.
Year : 1998
Volume : 8
Issue : 22
First Page : 3251
Last Page : 3256
Authors : Sheppard GS, Florjancic AS, Giesler JR, Xu L, Guo Y, Davidsen SK, Marcotte PA, Elmore I, Albert DH, Magoc TJ, Bouska JJ, Goodfellow CL, Morgan DW, Summers JB.
Abstract : A series of succinyl hydroxamate MMP inhibitors were prepared incorporating an aryl amino ketone moiety in place of the more typical C-terminal amino acid amides. Compounds of the C-terminal ketone series displayed potent inhibition of MMPs. Several compounds of the series were shown to be orally bioavailable.
|
In vitro inhibitory activity against human recombinant matrix metalloprotease 7
|
None
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Aryl ketones as novel replacements for the C-terminal amide bond of succinyl hydroxamate MMP inhibitors.
Year : 1998
Volume : 8
Issue : 22
First Page : 3251
Last Page : 3256
Authors : Sheppard GS, Florjancic AS, Giesler JR, Xu L, Guo Y, Davidsen SK, Marcotte PA, Elmore I, Albert DH, Magoc TJ, Bouska JJ, Goodfellow CL, Morgan DW, Summers JB.
Abstract : A series of succinyl hydroxamate MMP inhibitors were prepared incorporating an aryl amino ketone moiety in place of the more typical C-terminal amino acid amides. Compounds of the C-terminal ketone series displayed potent inhibition of MMPs. Several compounds of the series were shown to be orally bioavailable.
|
Inhibition of Matrix metalloprotease-2
|
Homo sapiens
|
1.8
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : General synthesis of alpha-substituted 3-bisaryloxy propionic acid derivatives as specific MMP inhibitors.
Year : 2001
Volume : 11
Issue : 3
First Page : 295
Last Page : 299
Authors : Chollet AM, Le Diguarher T, Murray L, Bertrand M, Tucker GC, Sabatini M, Pierré A, Atassi G, Bonnet J, Casara P.
Abstract : Modulations of alpha and aryl substitutions on 3-aryloxy propionic acid hydroxamates led to novel and potent inhibitors of MMP-2,3,9 and 13, and selectivity versus MMP-1.
|
Inhibitory activity against human Matrix metalloprotease-2
|
None
|
0.75
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : alpha-Alkyl-alpha-amino-beta-sulphone hydroxamates as potent MMP inhibitors that spare MMP-1.
Year : 2001
Volume : 11
Issue : 20
First Page : 2723
Last Page : 2725
Authors : Becker DP, DeCrescenzo G, Freskos J, Getman DP, Hockerman SL, Li M, Mehta P, Munie GE, Swearingen C.
Abstract : A series of alpha-alkyl-alpha-amino-beta-sulphone hydroxamates was prepared and evaluated for potency versus MMP-2 and MMP-13, and for selectivity versus MMP-1. Low nanomolar potency was obtained with selectivity versus MMP-1 ranging from >10 to >1000. Selected compounds were orally bioavailable.
|
50 percent inhibition of human Matrix metalloprotease-2 by the cleavage of fluorogenic peptide MCA-Pro-Leu-Gly-Leu-Dpa-ala-Arg-NH2
|
None
|
0.75
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of selective MMP inhibitors with an aryl backbone.
Year : 2000
Volume : 10
Issue : 24
First Page : 2815
Last Page : 2817
Authors : Barta TE, Becker DP, Bedell LJ, De Crescenzo GA, McDonald JJ, Munie GE, Rao S, Shieh HS, Stegeman R, Stevens AM, Villamil CI.
Abstract : A series of novel, MMP-1 sparing arylhydroxamate sulfonamides with activity against MMP-2 and -13 is described.
|
Inhibitory activity against matrix metalloprotease-2 (MMP2)
|
None
|
1.8
nM
|
|
Journal : J. Med. Chem.
Title : Stereospecific synthesis of 5-substituted 2-bisarylthiocyclopentane carboxylic acids as specific matrix metalloproteinase inhibitors.
Year : 2003
Volume : 46
Issue : 18
First Page : 3840
Last Page : 3852
Authors : Le Diguarher T, Chollet AM, Bertrand M, Hennig P, Raimbaud E, Sabatini M, Guilbaud N, Pierré A, Tucker GC, Casara P.
Abstract : The synthesis and structure-activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16-F10 metastasis model and display very good pharmacokinetic parameters.
|
In vitro selective inhibition against matrix metalloprotease-2 (MMP-2) using fluorimetric assay
|
None
|
0.41
nM
|
|
Journal : J. Med. Chem.
Title : Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors.
Year : 2002
Volume : 45
Issue : 1
First Page : 219
Last Page : 232
Authors : Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH, Albert DH, Bouska JJ, Elmore IN, Goodfellow CL, Marcotte PA, Tapang P, Morgan DW, Michaelides MR, Davidsen SK.
Abstract : A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
|
Inhibitory potency against Matrix metalloprotease-2 (MMP-2)
|
None
|
0.6
nM
|
|
Journal : J. Med. Chem.
Title : Beta-aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme.
Year : 2002
Volume : 45
Issue : 11
First Page : 2289
Last Page : 2293
Authors : Kottirsch G, Koch G, Feifel R, Neumann U.
Abstract : Novel hydroxamate inhibitors of tumor necrosis factor converting enzyme (TACE) and matrix metalloproteases (MMPs) have been synthesized via the Claisen-Ireland rearrangement. Aryl residues have been introduced to fill the enzyme's P1' specificity pocket. The best compound inhibits MMPs and TACE with nanomolar potency and inhibits the release of TNFalpha from cells with an IC50 of 48 nM. Oral administration to rats inhibits the LPS-induced plasma TNFalpha levels with an ED50 of 1 mg/kg.
|
Activity against Matrix metalloprotease-3 (MMP-3).
|
None
|
4.4
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket.
Year : 1998
Volume : 41
Issue : 8
First Page : 1209
Last Page : 1217
Authors : Yamamoto M, Tsujishita H, Hori N, Ohishi Y, Inoue S, Ikeda S, Okada Y.
Abstract : The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an alpha-branched alkyl group is critical for the binding toward DeltaMT1, while the introduction of a bulky group at the alpha-position of hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the data on the sensitivity of DeltaMT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of DeltaMT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against DeltaMT1 over MMP-1, but no selectivity between DeltaMT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.
|
Inhibition of Matrix metalloprotease-3
|
Homo sapiens
|
25.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : General synthesis of alpha-substituted 3-bisaryloxy propionic acid derivatives as specific MMP inhibitors.
Year : 2001
Volume : 11
Issue : 3
First Page : 295
Last Page : 299
Authors : Chollet AM, Le Diguarher T, Murray L, Bertrand M, Tucker GC, Sabatini M, Pierré A, Atassi G, Bonnet J, Casara P.
Abstract : Modulations of alpha and aryl substitutions on 3-aryloxy propionic acid hydroxamates led to novel and potent inhibitors of MMP-2,3,9 and 13, and selectivity versus MMP-1.
|
Inhibitory activity against matrix metalloprotease-3 (MMP3)
|
None
|
25.0
nM
|
|
Journal : J. Med. Chem.
Title : Stereospecific synthesis of 5-substituted 2-bisarylthiocyclopentane carboxylic acids as specific matrix metalloproteinase inhibitors.
Year : 2003
Volume : 46
Issue : 18
First Page : 3840
Last Page : 3852
Authors : Le Diguarher T, Chollet AM, Bertrand M, Hennig P, Raimbaud E, Sabatini M, Guilbaud N, Pierré A, Tucker GC, Casara P.
Abstract : The synthesis and structure-activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16-F10 metastasis model and display very good pharmacokinetic parameters.
|
Inhibition of recombinant human matrix metalloprotease-3
|
Homo sapiens
|
84.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure--activity relationships of azasugar-based MMP/ADAM inhibitors.
Year : 2003
Volume : 13
Issue : 16
First Page : 2737
Last Page : 2740
Authors : Moriyama H, Tsukida T, Inoue Y, Kondo H, Yoshino K, Nishimura S.
Abstract : In order to investigate structure-activity relationships of azasugar series toward metalloproteinases, we synthesized and evaluated several azasugar-based compounds. As a result, it was found that 4-phenoxybenzene derivative 3 having 2R,3R,4R,5S-configurations exhibited most potent inhibitory activities against matrix metalloproteinase-1, -3 and -9 and TACE.
|
Inhibition of recombinant human matrix metalloprotease-3
|
Homo sapiens
|
84.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of novel azasugar-based MMP/ADAM inhibitors.
Year : 2003
Volume : 13
Issue : 16
First Page : 2741
Last Page : 2744
Authors : Moriyama H, Tsukida T, Inoue Y, Kondo H, Yoshino K, Nishimura S.
Abstract : In order to verify whether azasugar would be a useful scaffold for inhibitory activity against metalloproteinases, we synthesized some azasugar-based compounds. As a result, it is clarified that azasugar moiety could function as successful inhibitor of matrix metalloproteinase-1, -3 and -9 and TACE.
|
Inhibition of human MMP-3.
|
Homo sapiens
|
2.4
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo.
Year : 2001
Volume : 44
Issue : 16
First Page : 2636
Last Page : 2660
Authors : Xue CB, Voss ME, Nelson DJ, Duan JJ, Cherney RJ, Jacobson IC, He X, Roderick J, Chen L, Corbett RL, Wang L, Meyer DT, Kennedy K, DeGradodagger WF, Hardman KD, Teleha CA, Jaffee BD, Liu RQ, Copeland RA, Covington MB, Christ DD, Trzaskos JM, Newton RC, Magolda RL, Wexler RR, Decicco CP.
Abstract : To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3'-P4' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC(50) values of </=0.2 microM in whole blood assay (WBA). Although the P3' area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3' was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3', an N-methylamide at P4' provided the best cyclophane analogue, SL422 (WBA IC(50) = 0.22 microM, LPS-mouse ED(50) = 15 mg/kg, po), whereas a morpholinylamide at P4' afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBA IC(50) = 0.067 microM, LPS-mouse ED(50) = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with K(i) values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.
|
Inhibition of Matrix metalloprotease-3 (MMP-3) in fluorimetric assay
|
None
|
14.0
nM
|
|
Journal : J. Med. Chem.
Title : Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors.
Year : 2002
Volume : 45
Issue : 1
First Page : 219
Last Page : 232
Authors : Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH, Albert DH, Bouska JJ, Elmore IN, Goodfellow CL, Marcotte PA, Tapang P, Morgan DW, Michaelides MR, Davidsen SK.
Abstract : A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
|
Inhibitory potency against Matrix metalloprotease-3 (MMP-3)
|
None
|
8.9
nM
|
|
Journal : J. Med. Chem.
Title : Beta-aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme.
Year : 2002
Volume : 45
Issue : 11
First Page : 2289
Last Page : 2293
Authors : Kottirsch G, Koch G, Feifel R, Neumann U.
Abstract : Novel hydroxamate inhibitors of tumor necrosis factor converting enzyme (TACE) and matrix metalloproteases (MMPs) have been synthesized via the Claisen-Ireland rearrangement. Aryl residues have been introduced to fill the enzyme's P1' specificity pocket. The best compound inhibits MMPs and TACE with nanomolar potency and inhibits the release of TNFalpha from cells with an IC50 of 48 nM. Oral administration to rats inhibits the LPS-induced plasma TNFalpha levels with an ED50 of 1 mg/kg.
|
Inhibition of Matrix metalloprotease-7 (MMP-7) in fluorimetric assay
|
None
|
4.1
nM
|
|
Journal : J. Med. Chem.
Title : Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors.
Year : 2002
Volume : 45
Issue : 1
First Page : 219
Last Page : 232
Authors : Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH, Albert DH, Bouska JJ, Elmore IN, Goodfellow CL, Marcotte PA, Tapang P, Morgan DW, Michaelides MR, Davidsen SK.
Abstract : A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
|
Inhibition of MMP-8 (matrix metalloprotease-8)
|
Homo sapiens
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors.
Year : 1999
Volume : 42
Issue : 23
First Page : 4890
Last Page : 4908
Authors : Barlaam B, Bird TG, Lambert-Van Der Brempt C, Campbell D, Foster SJ, Maciewicz R.
Abstract : Tumor necrosis factor alpha convertase (TACE), the enzyme responsible for the processing of pro-TNFalpha to TNFalpha, has been reported to be a metalloproteinase closely related to matrix metalloproteinases (MMPs). Current inhibitors of TACE such as succinate-based hydroxamic acids exemplified by Marimastat (TACE IC(50): 3.8 nM; blood IC(50): 7 microM) and BB1101 (TACE IC(50): 0.2 nM; blood IC(50): 2.3 microM) suffer from modest potency in blood and poor in vivo properties. The introduction of new bulky alpha-substituents into these succinate-based hydroxamic acids was studied. Substituents such as thioethers, sulfonamides, and ethers showed improved potency against TACE when compared with Marimastat. Although this improvement did not translate into better blood potency for thioether or ether substituents, the sulfonamide series exhibited improved potency both against TACE and in blood when compared with Marimastat. Optimization of this sulfonamide series has culminated in the identification of heterocyclic bicyclic sulfonamides such as 3t (TACE IC(50): 0.57 nM; blood IC(50): 0.28 microM).
|
Inhibition of Matrix metalloprotease-8 (MMP-8) in fluorimetric assay
|
None
|
0.47
nM
|
|
Journal : J. Med. Chem.
Title : Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors.
Year : 2002
Volume : 45
Issue : 1
First Page : 219
Last Page : 232
Authors : Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH, Albert DH, Bouska JJ, Elmore IN, Goodfellow CL, Marcotte PA, Tapang P, Morgan DW, Michaelides MR, Davidsen SK.
Abstract : A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
|
Activity against Matrix metalloprotease-9 (MMP-9).
|
None
|
8.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket.
Year : 1998
Volume : 41
Issue : 8
First Page : 1209
Last Page : 1217
Authors : Yamamoto M, Tsujishita H, Hori N, Ohishi Y, Inoue S, Ikeda S, Okada Y.
Abstract : The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an alpha-branched alkyl group is critical for the binding toward DeltaMT1, while the introduction of a bulky group at the alpha-position of hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the data on the sensitivity of DeltaMT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of DeltaMT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against DeltaMT1 over MMP-1, but no selectivity between DeltaMT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.
|
Inhibition of Matrix metalloprotease-9
|
Homo sapiens
|
1.6
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : General synthesis of alpha-substituted 3-bisaryloxy propionic acid derivatives as specific MMP inhibitors.
Year : 2001
Volume : 11
Issue : 3
First Page : 295
Last Page : 299
Authors : Chollet AM, Le Diguarher T, Murray L, Bertrand M, Tucker GC, Sabatini M, Pierré A, Atassi G, Bonnet J, Casara P.
Abstract : Modulations of alpha and aryl substitutions on 3-aryloxy propionic acid hydroxamates led to novel and potent inhibitors of MMP-2,3,9 and 13, and selectivity versus MMP-1.
|
Inhibitory activity against matrix metalloprotease-9 (MMP9)
|
None
|
1.6
nM
|
|
Journal : J. Med. Chem.
Title : Stereospecific synthesis of 5-substituted 2-bisarylthiocyclopentane carboxylic acids as specific matrix metalloproteinase inhibitors.
Year : 2003
Volume : 46
Issue : 18
First Page : 3840
Last Page : 3852
Authors : Le Diguarher T, Chollet AM, Bertrand M, Hennig P, Raimbaud E, Sabatini M, Guilbaud N, Pierré A, Tucker GC, Casara P.
Abstract : The synthesis and structure-activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16-F10 metastasis model and display very good pharmacokinetic parameters.
|
In vitro inhibition of human MMP-9.
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo.
Year : 2001
Volume : 44
Issue : 16
First Page : 2636
Last Page : 2660
Authors : Xue CB, Voss ME, Nelson DJ, Duan JJ, Cherney RJ, Jacobson IC, He X, Roderick J, Chen L, Corbett RL, Wang L, Meyer DT, Kennedy K, DeGradodagger WF, Hardman KD, Teleha CA, Jaffee BD, Liu RQ, Copeland RA, Covington MB, Christ DD, Trzaskos JM, Newton RC, Magolda RL, Wexler RR, Decicco CP.
Abstract : To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3'-P4' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC(50) values of </=0.2 microM in whole blood assay (WBA). Although the P3' area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3' was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3', an N-methylamide at P4' provided the best cyclophane analogue, SL422 (WBA IC(50) = 0.22 microM, LPS-mouse ED(50) = 15 mg/kg, po), whereas a morpholinylamide at P4' afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBA IC(50) = 0.067 microM, LPS-mouse ED(50) = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with K(i) values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.
|
Inhibition of recombinant human matrix metalloprotease-9
|
Homo sapiens
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure--activity relationships of azasugar-based MMP/ADAM inhibitors.
Year : 2003
Volume : 13
Issue : 16
First Page : 2737
Last Page : 2740
Authors : Moriyama H, Tsukida T, Inoue Y, Kondo H, Yoshino K, Nishimura S.
Abstract : In order to investigate structure-activity relationships of azasugar series toward metalloproteinases, we synthesized and evaluated several azasugar-based compounds. As a result, it was found that 4-phenoxybenzene derivative 3 having 2R,3R,4R,5S-configurations exhibited most potent inhibitory activities against matrix metalloproteinase-1, -3 and -9 and TACE.
|
Inhibition of recombinant human matrix metalloprotease-9 (gelatinase B)
|
Homo sapiens
|
11.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of novel azasugar-based MMP/ADAM inhibitors.
Year : 2003
Volume : 13
Issue : 16
First Page : 2741
Last Page : 2744
Authors : Moriyama H, Tsukida T, Inoue Y, Kondo H, Yoshino K, Nishimura S.
Abstract : In order to verify whether azasugar would be a useful scaffold for inhibitory activity against metalloproteinases, we synthesized some azasugar-based compounds. As a result, it is clarified that azasugar moiety could function as successful inhibitor of matrix metalloproteinase-1, -3 and -9 and TACE.
|
In vitro selective inhibition against Matrix metalloprotease-9 (MMP-9) using fluorimetric assay
|
None
|
0.79
nM
|
|
Journal : J. Med. Chem.
Title : Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors.
Year : 2002
Volume : 45
Issue : 1
First Page : 219
Last Page : 232
Authors : Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH, Albert DH, Bouska JJ, Elmore IN, Goodfellow CL, Marcotte PA, Tapang P, Morgan DW, Michaelides MR, Davidsen SK.
Abstract : A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
|
50% inhibition of human recombinant Matrilysin
|
None
|
20.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Inhibition of Matrix Metalloproteinases: An examination of the S1 pocket
Year : 1997
Volume : 7
Issue : 2
First Page : 193
Last Page : 198
Authors : Miller A, Askew M, Beckett R, Bellamy CL, Bone EA, Coates RE, Davidson AH, Drummond AH, Huxley P, Martin FM, Saroglou L, Thompson AJ, van Dijk SE, Whittaker M
|
Activity against Matrix metalloprotease-1 (MMP-1).
|
None
|
2.0
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket.
Year : 1998
Volume : 41
Issue : 8
First Page : 1209
Last Page : 1217
Authors : Yamamoto M, Tsujishita H, Hori N, Ohishi Y, Inoue S, Ikeda S, Okada Y.
Abstract : The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an alpha-branched alkyl group is critical for the binding toward DeltaMT1, while the introduction of a bulky group at the alpha-position of hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the data on the sensitivity of DeltaMT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of DeltaMT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against DeltaMT1 over MMP-1, but no selectivity between DeltaMT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.
|
Inhibitory activity against MMP-1 (Matrix metalloprotease-1)
|
None
|
5.0
nM
|
|
Journal : J. Med. Chem.
Title : New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors.
Year : 1999
Volume : 42
Issue : 23
First Page : 4890
Last Page : 4908
Authors : Barlaam B, Bird TG, Lambert-Van Der Brempt C, Campbell D, Foster SJ, Maciewicz R.
Abstract : Tumor necrosis factor alpha convertase (TACE), the enzyme responsible for the processing of pro-TNFalpha to TNFalpha, has been reported to be a metalloproteinase closely related to matrix metalloproteinases (MMPs). Current inhibitors of TACE such as succinate-based hydroxamic acids exemplified by Marimastat (TACE IC(50): 3.8 nM; blood IC(50): 7 microM) and BB1101 (TACE IC(50): 0.2 nM; blood IC(50): 2.3 microM) suffer from modest potency in blood and poor in vivo properties. The introduction of new bulky alpha-substituents into these succinate-based hydroxamic acids was studied. Substituents such as thioethers, sulfonamides, and ethers showed improved potency against TACE when compared with Marimastat. Although this improvement did not translate into better blood potency for thioether or ether substituents, the sulfonamide series exhibited improved potency both against TACE and in blood when compared with Marimastat. Optimization of this sulfonamide series has culminated in the identification of heterocyclic bicyclic sulfonamides such as 3t (TACE IC(50): 0.57 nM; blood IC(50): 0.28 microM).
|
Inhibitory activity against human Matrix metalloprotease-1
|
None
|
2.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : alpha-Alkyl-alpha-amino-beta-sulphone hydroxamates as potent MMP inhibitors that spare MMP-1.
Year : 2001
Volume : 11
Issue : 20
First Page : 2723
Last Page : 2725
Authors : Becker DP, DeCrescenzo G, Freskos J, Getman DP, Hockerman SL, Li M, Mehta P, Munie GE, Swearingen C.
Abstract : A series of alpha-alkyl-alpha-amino-beta-sulphone hydroxamates was prepared and evaluated for potency versus MMP-2 and MMP-13, and for selectivity versus MMP-1. Low nanomolar potency was obtained with selectivity versus MMP-1 ranging from >10 to >1000. Selected compounds were orally bioavailable.
|
Inhibition of Matrix metalloprotease-1
|
Homo sapiens
|
1.5
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : General synthesis of alpha-substituted 3-bisaryloxy propionic acid derivatives as specific MMP inhibitors.
Year : 2001
Volume : 11
Issue : 3
First Page : 295
Last Page : 299
Authors : Chollet AM, Le Diguarher T, Murray L, Bertrand M, Tucker GC, Sabatini M, Pierré A, Atassi G, Bonnet J, Casara P.
Abstract : Modulations of alpha and aryl substitutions on 3-aryloxy propionic acid hydroxamates led to novel and potent inhibitors of MMP-2,3,9 and 13, and selectivity versus MMP-1.
|
50 percent inhibition of human Matrix metalloprotease-1 by the cleavage of fluorogenic peptide MCA-Pro-Leu-Gly-Leu-Dpa-ala-Arg-NH2
|
None
|
2.9
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of selective MMP inhibitors with an aryl backbone.
Year : 2000
Volume : 10
Issue : 24
First Page : 2815
Last Page : 2817
Authors : Barta TE, Becker DP, Bedell LJ, De Crescenzo GA, McDonald JJ, Munie GE, Rao S, Shieh HS, Stegeman R, Stevens AM, Villamil CI.
Abstract : A series of novel, MMP-1 sparing arylhydroxamate sulfonamides with activity against MMP-2 and -13 is described.
|
Inhibitory activity against matrix metalloprotease-1 (MMP1)
|
None
|
1.5
nM
|
|
Journal : J. Med. Chem.
Title : Stereospecific synthesis of 5-substituted 2-bisarylthiocyclopentane carboxylic acids as specific matrix metalloproteinase inhibitors.
Year : 2003
Volume : 46
Issue : 18
First Page : 3840
Last Page : 3852
Authors : Le Diguarher T, Chollet AM, Bertrand M, Hennig P, Raimbaud E, Sabatini M, Guilbaud N, Pierré A, Tucker GC, Casara P.
Abstract : The synthesis and structure-activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16-F10 metastasis model and display very good pharmacokinetic parameters.
|
Inhibition of recombinant human matrix metalloprotease-1
|
Homo sapiens
|
1.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure--activity relationships of azasugar-based MMP/ADAM inhibitors.
Year : 2003
Volume : 13
Issue : 16
First Page : 2737
Last Page : 2740
Authors : Moriyama H, Tsukida T, Inoue Y, Kondo H, Yoshino K, Nishimura S.
Abstract : In order to investigate structure-activity relationships of azasugar series toward metalloproteinases, we synthesized and evaluated several azasugar-based compounds. As a result, it was found that 4-phenoxybenzene derivative 3 having 2R,3R,4R,5S-configurations exhibited most potent inhibitory activities against matrix metalloproteinase-1, -3 and -9 and TACE.
|
Inhibition of Recombinant human matrix metalloprotease-1
|
Homo sapiens
|
1.1
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of novel azasugar-based MMP/ADAM inhibitors.
Year : 2003
Volume : 13
Issue : 16
First Page : 2741
Last Page : 2744
Authors : Moriyama H, Tsukida T, Inoue Y, Kondo H, Yoshino K, Nishimura S.
Abstract : In order to verify whether azasugar would be a useful scaffold for inhibitory activity against metalloproteinases, we synthesized some azasugar-based compounds. As a result, it is clarified that azasugar moiety could function as successful inhibitor of matrix metalloproteinase-1, -3 and -9 and TACE.
|
In vitro inhibition of human MMP-1.
|
None
|
1.0
nM
|
|
Journal : J. Med. Chem.
Title : Design, synthesis, and structure-activity relationships of macrocyclic hydroxamic acids that inhibit tumor necrosis factor alpha release in vitro and in vivo.
Year : 2001
Volume : 44
Issue : 16
First Page : 2636
Last Page : 2660
Authors : Xue CB, Voss ME, Nelson DJ, Duan JJ, Cherney RJ, Jacobson IC, He X, Roderick J, Chen L, Corbett RL, Wang L, Meyer DT, Kennedy K, DeGradodagger WF, Hardman KD, Teleha CA, Jaffee BD, Liu RQ, Copeland RA, Covington MB, Christ DD, Trzaskos JM, Newton RC, Magolda RL, Wexler RR, Decicco CP.
Abstract : To search for TNF-alpha (tumor necrosis factor alpha) converting enzyme (TACE) inhibitors, we designed a new class of macrocyclic hydroxamic acids by linking the P1 and P2' residues of acyclic anti-succinate-based hydroxamic acids. A variety of residues including amide, carbamate, alkyl, sulfonamido, Boc-amino, and amino were found to be suitable P1-P2' linkers. With an N-methylamide at P3', the 13-16-membered macrocycles prepared exhibited low micromolar activities in the inhibition of TNF-alpha release from LPS-stimulated human whole blood. Further elaboration in the P3'-P4' area using the cyclophane and cyclic carbamate templates led to the identification of a number of potent analogues with IC(50) values of </=0.2 microM in whole blood assay (WBA). Although the P3' area can accommodate a broad array of structurally diversified functional groups including polar residues, hydrophobic residues, and amino and carboxylic acid moieties, in both the cyclophane series and the cyclic carbamate series, a glycine residue at P3' was identified as a critical structural component to achieve both good in vitro potency and good oral activity. With a glycine residue at P3', an N-methylamide at P4' provided the best cyclophane analogue, SL422 (WBA IC(50) = 0.22 microM, LPS-mouse ED(50) = 15 mg/kg, po), whereas a morpholinylamide at P4' afforded the most potent and most orally active cyclic carbamate analogue, SP057 (WBA IC(50) = 0.067 microM, LPS-mouse ED(50) = 2.3 mg/kg, po). Further profiling for SL422 and SP057 showed that these macrocyclic compounds are potent TACE inhibitors, with K(i) values of 12 and 4.2 nM in the porcine TACE assay, and are broad-spectrum MMP inhibitors. Pharmacokinetic studies in beagle dogs revealed that SL422 and SP057 are orally bioavailable, with oral bioavailabilities of 11% and 23%, respectively.
|
In vitro selective inhibition against matrix metalloprotease-1 (MMP-1) using a fluorimetric assay
|
None
|
0.78
nM
|
|
Journal : J. Med. Chem.
Title : Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors.
Year : 2002
Volume : 45
Issue : 1
First Page : 219
Last Page : 232
Authors : Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH, Albert DH, Bouska JJ, Elmore IN, Goodfellow CL, Marcotte PA, Tapang P, Morgan DW, Michaelides MR, Davidsen SK.
Abstract : A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
|
Inhibitory potency against Matrix metalloprotease-1 (MMP-1)
|
None
|
0.7
nM
|
|
Journal : J. Med. Chem.
Title : Beta-aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme.
Year : 2002
Volume : 45
Issue : 11
First Page : 2289
Last Page : 2293
Authors : Kottirsch G, Koch G, Feifel R, Neumann U.
Abstract : Novel hydroxamate inhibitors of tumor necrosis factor converting enzyme (TACE) and matrix metalloproteases (MMPs) have been synthesized via the Claisen-Ireland rearrangement. Aryl residues have been introduced to fill the enzyme's P1' specificity pocket. The best compound inhibits MMPs and TACE with nanomolar potency and inhibits the release of TNFalpha from cells with an IC50 of 48 nM. Oral administration to rats inhibits the LPS-induced plasma TNFalpha levels with an ED50 of 1 mg/kg.
|
Inhibition of Matrix metalloprotease-13
|
Homo sapiens
|
3.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : General synthesis of alpha-substituted 3-bisaryloxy propionic acid derivatives as specific MMP inhibitors.
Year : 2001
Volume : 11
Issue : 3
First Page : 295
Last Page : 299
Authors : Chollet AM, Le Diguarher T, Murray L, Bertrand M, Tucker GC, Sabatini M, Pierré A, Atassi G, Bonnet J, Casara P.
Abstract : Modulations of alpha and aryl substitutions on 3-aryloxy propionic acid hydroxamates led to novel and potent inhibitors of MMP-2,3,9 and 13, and selectivity versus MMP-1.
|
Inhibitory activity against human Matrix metalloprotease-13
|
None
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : alpha-Alkyl-alpha-amino-beta-sulphone hydroxamates as potent MMP inhibitors that spare MMP-1.
Year : 2001
Volume : 11
Issue : 20
First Page : 2723
Last Page : 2725
Authors : Becker DP, DeCrescenzo G, Freskos J, Getman DP, Hockerman SL, Li M, Mehta P, Munie GE, Swearingen C.
Abstract : A series of alpha-alkyl-alpha-amino-beta-sulphone hydroxamates was prepared and evaluated for potency versus MMP-2 and MMP-13, and for selectivity versus MMP-1. Low nanomolar potency was obtained with selectivity versus MMP-1 ranging from >10 to >1000. Selected compounds were orally bioavailable.
|
50 percent inhibition of human Matrix metalloprotease-13 by the cleavage of fluorogenic peptide MCA-Pro-Leu-Gly-Leu-Dpa-ala-Arg-NH2
|
None
|
2.0
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Synthesis and activity of selective MMP inhibitors with an aryl backbone.
Year : 2000
Volume : 10
Issue : 24
First Page : 2815
Last Page : 2817
Authors : Barta TE, Becker DP, Bedell LJ, De Crescenzo GA, McDonald JJ, Munie GE, Rao S, Shieh HS, Stegeman R, Stevens AM, Villamil CI.
Abstract : A series of novel, MMP-1 sparing arylhydroxamate sulfonamides with activity against MMP-2 and -13 is described.
|
Inhibitory activity against matrix metalloprotease-13 (MMP13)
|
None
|
3.4
nM
|
|
Journal : J. Med. Chem.
Title : Stereospecific synthesis of 5-substituted 2-bisarylthiocyclopentane carboxylic acids as specific matrix metalloproteinase inhibitors.
Year : 2003
Volume : 46
Issue : 18
First Page : 3840
Last Page : 3852
Authors : Le Diguarher T, Chollet AM, Bertrand M, Hennig P, Raimbaud E, Sabatini M, Guilbaud N, Pierré A, Tucker GC, Casara P.
Abstract : The synthesis and structure-activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16-F10 metastasis model and display very good pharmacokinetic parameters.
|
Inhibition of Matrix metalloprotease-13 (MMP-13) in fluorimetric assay
|
None
|
1.2
nM
|
|
Journal : J. Med. Chem.
Title : Phenoxyphenyl sulfone N-formylhydroxylamines (retrohydroxamates) as potent, selective, orally bioavailable matrix metalloproteinase inhibitors.
Year : 2002
Volume : 45
Issue : 1
First Page : 219
Last Page : 232
Authors : Wada CK, Holms JH, Curtin ML, Dai Y, Florjancic AS, Garland RB, Guo Y, Heyman HR, Stacey JR, Steinman DH, Albert DH, Bouska JJ, Elmore IN, Goodfellow CL, Marcotte PA, Tapang P, Morgan DW, Michaelides MR, Davidsen SK.
Abstract : A novel series of sulfone N-formylhydroxylamines (retrohydroxamates) have been investigated as matrix metalloproteinases (MMP) inhibitors. The substitution of the ether linkage of ABT-770 (5) with a sulfone group 13a led to a substantial increase in activity against MMP-9 but was accompanied by a loss of selectivity for inhibition of MMP-2 and -9 over MMP-1 and diminished oral exposure. Replacement of the biphenyl P1' substituent with a phenoxyphenyl group provided compounds that are highly selective for inhibition of MMP-2 and -9 over MMP-1. Optimization of the substituent adjacent to the retrohydroxamate center in this series led to the clinical candidate ABT-518 (6), a highly potent, selective, orally bioavailable MMP inhibitor that has been shown to significantly inhibit tumor growth in animal cancer models.
|
Activity against Matrix metalloprotease-2 (MMP-2).
|
None
|
5.1
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket.
Year : 1998
Volume : 41
Issue : 8
First Page : 1209
Last Page : 1217
Authors : Yamamoto M, Tsujishita H, Hori N, Ohishi Y, Inoue S, Ikeda S, Okada Y.
Abstract : The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an alpha-branched alkyl group is critical for the binding toward DeltaMT1, while the introduction of a bulky group at the alpha-position of hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the data on the sensitivity of DeltaMT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of DeltaMT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against DeltaMT1 over MMP-1, but no selectivity between DeltaMT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.
|
Percent inhibition against B16-F10 mouse melanoma tested in vivo at 30 mg/kg
|
Mus musculus
|
40.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Arylsulphonyl hydroxamic acids: potent and selective matrix metalloproteinase inhibitors.
Year : 2001
Volume : 11
Issue : 11
First Page : 1465
Last Page : 1468
Authors : Baxter AD, Bhogal R, Bird J, Keily JF, Manallack DT, Montana JG, Owen DA, Pitt WR, Watson RJ, Wills RE.
Abstract : A series of novel matrix metalloproteinase inhibitors is described in which selectivity between MMP and 'sheddase' activity has been achieved and which demonstrate potent in vivo activity in models of arthritis and cancer.
|
Compound was tested for inhibition of Tumor Necrosis Factor production in rat at a peroral dose of 10 mg/kg
|
Rattus norvegicus
|
69.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen rearrangement.
Year : 1998
Volume : 8
Issue : 11
First Page : 1359
Last Page : 1364
Authors : Pratt LM, Beckett RP, Bellamy CL, Corkill DJ, Cossins J, Courtney PF, Davies SJ, Davidson AH, Drummond AH, Helfrich K, Lewis CN, Mangan M, Martin FM, Miller K, Nayee P, Ricketts ML, Thomas W, Todd RS, Whittaker M.
Abstract : Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.
|
Compound was tested for inhibition of Tumor Necrosis Factor production in rat at a peroral dose of 2.5 mg/kg
|
Rattus norvegicus
|
11.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen rearrangement.
Year : 1998
Volume : 8
Issue : 11
First Page : 1359
Last Page : 1364
Authors : Pratt LM, Beckett RP, Bellamy CL, Corkill DJ, Cossins J, Courtney PF, Davies SJ, Davidson AH, Drummond AH, Helfrich K, Lewis CN, Mangan M, Martin FM, Miller K, Nayee P, Ricketts ML, Thomas W, Todd RS, Whittaker M.
Abstract : Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.
|
Compound was tested for inhibition of Tumor Necrosis Factor production in rat at a peroral dose of 5 mg/kg
|
Rattus norvegicus
|
50.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : The synthesis of novel matrix metalloproteinase inhibitors employing the Ireland-Claisen rearrangement.
Year : 1998
Volume : 8
Issue : 11
First Page : 1359
Last Page : 1364
Authors : Pratt LM, Beckett RP, Bellamy CL, Corkill DJ, Cossins J, Courtney PF, Davies SJ, Davidson AH, Drummond AH, Helfrich K, Lewis CN, Mangan M, Martin FM, Miller K, Nayee P, Ricketts ML, Thomas W, Todd RS, Whittaker M.
Abstract : Matrix metalloproteinase inhibitors of general formula (1) were synthesised by a route involving an Ireland-Claisen rearrangement which enables systematic modification of the substituent alpha to the hydroxamic acid. An analogue (12c) possessing an alpha-cyclopentyl group is a potent broad spectrum inhibitor that displays high and sustained blood levels following oral dosing in both the rat and marmoset ex-vivo bioassays. This compound and analogues are also potent inhibitors of TNF alpha release.
|
Percent inhibition against adjuvant arthritis in rats tested in vivo at 10 mg/kg
|
Rattus norvegicus
|
50.0
%
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Arylsulphonyl hydroxamic acids: potent and selective matrix metalloproteinase inhibitors.
Year : 2001
Volume : 11
Issue : 11
First Page : 1465
Last Page : 1468
Authors : Baxter AD, Bhogal R, Bird J, Keily JF, Manallack DT, Montana JG, Owen DA, Pitt WR, Watson RJ, Wills RE.
Abstract : A series of novel matrix metalloproteinase inhibitors is described in which selectivity between MMP and 'sheddase' activity has been achieved and which demonstrate potent in vivo activity in models of arthritis and cancer.
|
Inhibition of recombinant human TNF-alpha converting enzyme (TACE)
|
Homo sapiens
|
0.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Structure--activity relationships of azasugar-based MMP/ADAM inhibitors.
Year : 2003
Volume : 13
Issue : 16
First Page : 2737
Last Page : 2740
Authors : Moriyama H, Tsukida T, Inoue Y, Kondo H, Yoshino K, Nishimura S.
Abstract : In order to investigate structure-activity relationships of azasugar series toward metalloproteinases, we synthesized and evaluated several azasugar-based compounds. As a result, it was found that 4-phenoxybenzene derivative 3 having 2R,3R,4R,5S-configurations exhibited most potent inhibitory activities against matrix metalloproteinase-1, -3 and -9 and TACE.
|
Inhibitory potency against Tumor necrosis factor alpha converting enzyme (TACE)
|
Homo sapiens
|
6.3
nM
|
|
Journal : J. Med. Chem.
Title : Beta-aryl-succinic acid hydroxamates as dual inhibitors of matrix metalloproteinases and tumor necrosis factor alpha converting enzyme.
Year : 2002
Volume : 45
Issue : 11
First Page : 2289
Last Page : 2293
Authors : Kottirsch G, Koch G, Feifel R, Neumann U.
Abstract : Novel hydroxamate inhibitors of tumor necrosis factor converting enzyme (TACE) and matrix metalloproteases (MMPs) have been synthesized via the Claisen-Ireland rearrangement. Aryl residues have been introduced to fill the enzyme's P1' specificity pocket. The best compound inhibits MMPs and TACE with nanomolar potency and inhibits the release of TNFalpha from cells with an IC50 of 48 nM. Oral administration to rats inhibits the LPS-induced plasma TNFalpha levels with an ED50 of 1 mg/kg.
|
Inhibitory activity against Tumor necrosis factor alpha-converting enzyme (TACE) in blood.
|
None
|
3.8
nM
|
|
Journal : J. Med. Chem.
Title : New alpha-substituted succinate-based hydroxamic acids as TNFalpha convertase inhibitors.
Year : 1999
Volume : 42
Issue : 23
First Page : 4890
Last Page : 4908
Authors : Barlaam B, Bird TG, Lambert-Van Der Brempt C, Campbell D, Foster SJ, Maciewicz R.
Abstract : Tumor necrosis factor alpha convertase (TACE), the enzyme responsible for the processing of pro-TNFalpha to TNFalpha, has been reported to be a metalloproteinase closely related to matrix metalloproteinases (MMPs). Current inhibitors of TACE such as succinate-based hydroxamic acids exemplified by Marimastat (TACE IC(50): 3.8 nM; blood IC(50): 7 microM) and BB1101 (TACE IC(50): 0.2 nM; blood IC(50): 2.3 microM) suffer from modest potency in blood and poor in vivo properties. The introduction of new bulky alpha-substituents into these succinate-based hydroxamic acids was studied. Substituents such as thioethers, sulfonamides, and ethers showed improved potency against TACE when compared with Marimastat. Although this improvement did not translate into better blood potency for thioether or ether substituents, the sulfonamide series exhibited improved potency both against TACE and in blood when compared with Marimastat. Optimization of this sulfonamide series has culminated in the identification of heterocyclic bicyclic sulfonamides such as 3t (TACE IC(50): 0.57 nM; blood IC(50): 0.28 microM).
|
Inhibition of recombinant human tumor necrosis factor-alpha converting enzyme
|
Homo sapiens
|
0.4
nM
|
|
Journal : Bioorg. Med. Chem. Lett.
Title : Design, synthesis and evaluation of novel azasugar-based MMP/ADAM inhibitors.
Year : 2003
Volume : 13
Issue : 16
First Page : 2741
Last Page : 2744
Authors : Moriyama H, Tsukida T, Inoue Y, Kondo H, Yoshino K, Nishimura S.
Abstract : In order to verify whether azasugar would be a useful scaffold for inhibitory activity against metalloproteinases, we synthesized some azasugar-based compounds. As a result, it is clarified that azasugar moiety could function as successful inhibitor of matrix metalloproteinase-1, -3 and -9 and TACE.
|
Activity against deletion mutant of MT1-MMP lacking the transmembrane domain (deltaMT1)
|
None
|
1.82
nM
|
|
Journal : J. Med. Chem.
Title : Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket.
Year : 1998
Volume : 41
Issue : 8
First Page : 1209
Last Page : 1217
Authors : Yamamoto M, Tsujishita H, Hori N, Ohishi Y, Inoue S, Ikeda S, Okada Y.
Abstract : The membrane-type 1 matrix metalloproteinase (MT1-MMP) has been reported to mediate the activation of pro-gelatinase A (proMMP-2), which is associated with tumor proliferation and metastasis. MT1-MMP can also digest extracellular matrix (ECM) such as interstitial collagens, gelatin, and proteoglycan and thus may play an important role in pathophysiological digestion of ECM. We studied the inhibitory effect of various hydroxamate MMP inhibitors, including known inhibitors such as BB-94, BB-2516, GM6001, and Ro31-9790, on a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) to further characterize the enzyme and develop a selective inhibitor for MT1-MMP. The evaluation of the inhibitory activities of various hydroxamates reveals general structural profiles affecting selectivities toward MMPs. In particular, a longer side chain at the P1' position is preferable for the binding to MMP-2, -3, and -9 and MT1-MMP. For the P2' position, an alpha-branched alkyl group is critical for the binding toward DeltaMT1, while the introduction of a bulky group at the alpha-position of hydroxamic acid seems to diminish the activity against DeltaMT1. Summation of the data on the sensitivity of DeltaMT1 to various hydroxamate inhibitors indicates that (1) the volume of the S1' subsite of DeltaMT1 is similar to that of MMP-2, -3, and -9, which is bigger than that of MMP-1, and (2) the S1 and S2' subsites are narrower than those in other MMPs. On the basis of these results, the hydroxamates with a P1' phenylpropyl and P2' alpha-branched alkyl group were synthesized and evaluated for inhibitory activity. These inhibitors (1h,i) showed strong activity against DeltaMT1 over MMP-1, but no selectivity between DeltaMT1 and MMP-9. These results are explained using molecular modeling studies conducted on MT1-MMP.
|
Inhibition of TACE
|
None
|
3.8
nM
|
|
Journal : Bioorg. Med. Chem.
Title : Current perspective of TACE inhibitors: a review.
Year : 2009
Volume : 17
Issue : 2
First Page : 444
Last Page : 459
Authors : DasGupta S, Murumkar PR, Giridhar R, Yadav MR.
Abstract : Rheumatoid Arthritis (RA) is one of the most common autoimmune inflammatory conditions, affecting approximately 1% of the adult population worldwide. TNF-alpha is a pleitropic, pro-inflammatory cytokine which plays a pivotal role in the origin and progression of RA and other immune mediated disorders. The success of anti-TNF-alpha biological agents proved that inhibition of TNF-alpha could result in effective control of RA. Since the discovery of anti-TNF-alpha biologicals, much efforts have gone into developing an orally bioavailable small size TNF-alpha antagonist. One of the ways to block TNF-alpha in biological fluids is to inhibit TNF-alpha converting enzyme (TACE). This target has been validated in preclinical trials using TACE inhibitors. But, even after more than a decade no single TACE inhibitor has passed the Phase II clinical trials. Very recently, it has been shown that TACE inhibitors could also be used for inhibition of pathogenic EGFR signaling in cancer. Hence, TACE inhibitors could perform a dual role, in curing not only RA but also certain cancerous conditions. Developments in the field have prompted us to review the research work on TACE inhibitors, especially their structure activity relationships and molecular modeling studies.
|
PubChem BioAssay. QFRET-based biochemical high throughput dose response assay to identify exosite inhibitors of ADAM10.. (Class of assay: confirmatory)
|
None
|
60.65
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. QFRET-based biochemical high throughput dose response assay to identify exosite inhibitors of ADAM17. (Class of assay: confirmatory)
|
None
|
11.47
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. Counterscreen for exosite inhibitors of ADAM17: Fluorescence resonance energy transfer (FRET)-based biochemical high throughput dose response assay to identify inhibitors of ADAM10. (Class of assay: confirmatory)
|
None
|
35.76
nM
|
|
Title : PubChem BioAssay data set
|
PubChem BioAssay. Counterscreen for exosite inhibitors of ADAM10: QFRET-based biochemical high throughput dose response assay to identify inhibitors of ADAM17. (Class of assay: confirmatory)
|
None
|
25.41
nM
|
|
Title : PubChem BioAssay data set
|
Inhibition of ADAM17 in human THP1 cells assessed as inhibition of LPS-stimulated TNFalpha cleavage at 10 uM after 1 hr by AlphaScreen assay relative to control
|
Homo sapiens
|
30.0
%
|
|
Journal : J. Med. Chem.
Title : SAR Studies of Exosite-Binding Substrate-Selective Inhibitors of A Disintegrin And Metalloprotease 17 (ADAM17) and Application as Selective in Vitro Probes.
Year : 2015
Volume : 58
Issue : 15
First Page : 5808
Last Page : 5824
Authors : Knapinska AM, Dreymuller D, Ludwig A, Smith L, Golubkov V, Sohail A, Fridman R, Giulianotti M, LaVoi TM, Houghten RA, Fields GB, Minond D.
Abstract : ADAM17 is implicated in several debilitating diseases. However, drug discovery efforts targeting ADAM17 have failed due to the utilization of zinc-binding inhibitors. We previously reported discovery of highly selective nonzinc-binding exosite-targeting inhibitors of ADAM17 that exhibited not only enzyme isoform selectivity but synthetic substrate selectivity as well ( J. Biol. Chem. 2013, 288, 22871). As a result of SAR studies presented herein, we obtained several highly selective ADAM17 inhibitors, six of which were further characterized in biochemical and cell-based assays. Lead compounds exhibited low cellular toxicity and high potency and selectivity for ADAM17. In addition, several of the leads inhibited ADAM17 in a substrate-selective manner, which has not been previously documented for inhibitors of the ADAM family. These findings suggest that targeting exosites of ADAM17 can be used to obtain highly desirable substrate-selective inhibitors. Additionally, current inhibitors can be used as probes of biological activity of ADAM17 in various in vitro and, potentially, in vivo systems.
|
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
|
68.66
%
|
|
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 MMP2 (unknown origin) preincubated for 1 hr followed by (QF)-24 substrate addition measured at 1 min time interval for 1 hr by fluorescence assay
|
Homo sapiens
|
0.43
nM
|
|
Journal : J Med Chem
Title : Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases.
Year : 2019
Volume : 62
Issue : 2
First Page : 622
Last Page : 640
Authors : Vinh NB, Drinkwater N, Malcolm TR, Kassiou M, Lucantoni L, Grin PM, Butler GS, Duffy S, Overall CM, Avery VM, Scammells PJ, McGowan S.
Abstract : There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum ( Pf-M1 and Pf-M17) and P. vivax ( Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.
|
Inhibition of MMP9 (unknown origin) preincubated for 1 hr followed by (QF)-24 substrate addition measured at 1 min time interval for 1 hr by fluorescence assay
|
Homo sapiens
|
3.1
nM
|
|
Journal : J Med Chem
Title : Hydroxamic Acid Inhibitors Provide Cross-Species Inhibition of Plasmodium M1 and M17 Aminopeptidases.
Year : 2019
Volume : 62
Issue : 2
First Page : 622
Last Page : 640
Authors : Vinh NB, Drinkwater N, Malcolm TR, Kassiou M, Lucantoni L, Grin PM, Butler GS, Duffy S, Overall CM, Avery VM, Scammells PJ, McGowan S.
Abstract : There is an urgent clinical need for antimalarial compounds that target malaria caused by both Plasmodium falciparum and Plasmodium vivax. The M1 and M17 metalloexopeptidases play key roles in Plasmodium hemoglobin digestion and are validated drug targets. We used a multitarget strategy to rationally design inhibitors capable of potent inhibition of the M1 and M17 aminopeptidases from both P. falciparum ( Pf-M1 and Pf-M17) and P. vivax ( Pv-M1 and Pv-M17). The novel chemical series contains a hydroxamic acid zinc binding group to coordinate catalytic zinc ion/s, and a variety of hydrophobic groups to probe the S1' pockets of the four target enzymes. Structural characterization by cocrystallization showed that selected compounds utilize new and unexpected binding modes; most notably, compounds substituted with bulky hydrophobic substituents displace the Pf-M17 catalytic zinc ion. Excitingly, key compounds of the series potently inhibit all four molecular targets and show antimalarial activity comparable to current clinical candidates.
|
Inhibition of MMP2 (unknown origin) using QF-24 as substrate preincubated for 1 hr followed by substrate addition and measured at 1 min interval for 1 hr by fluorescence assay
|
Homo sapiens
|
0.43
nM
|
|
Journal : J Med Chem
Title : Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions.
Year : 2019
Volume : 62
Issue : 15
First Page : 7185
Last Page : 7209
Authors : Lee J, Vinh NB, Drinkwater N, Yang W, Kannan Sivaraman K, Schembri LS, Gazdik M, Grin PM, Butler GS, Overall CM, Charman SA, McGowan S, Scammells PJ.
Abstract : Aminopeptidase N (APN/CD13) is a zinc-dependent M1 aminopeptidase that contributes to cancer progression by promoting angiogenesis, metastasis, and tumor invasion. We have previously identified hydroxamic acid-containing analogues that are potent inhibitors of the APN homologue from the malarial parasite Plasmodium falciparum M1 aminopeptidase (PfA-M1). Herein, we describe the rationale that underpins the repurposing of PfA-M1 inhibitors as novel APN inhibitors. A series of novel hydroxamic acid analogues were developed using a structure-based design approach and evaluated their inhibition activities against APN. N-(2-(Hydroxyamino)-2-oxo-1-(3',4',5'-trifluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide (6ad) proved to be an extremely potent inhibitor of APN activity in vitro, selective against other zinc-dependent enzymes such as matrix metalloproteases, and possessed limited cytotoxicity against Ad293 cells and favorable physicochemical and metabolic stability properties. The combined results indicate that compound 6ad may be a useful lead for the development of anticancer agents.
|
Inhibition of MMP9 (unknown origin) using QF-24 as substrate preincubated for 1 hr followed by substrate addition and measured at 1 min interval for 1 hr by fluorescence assay
|
Homo sapiens
|
3.1
nM
|
|
Journal : J Med Chem
Title : Novel Human Aminopeptidase N Inhibitors: Discovery and Optimization of Subsite Binding Interactions.
Year : 2019
Volume : 62
Issue : 15
First Page : 7185
Last Page : 7209
Authors : Lee J, Vinh NB, Drinkwater N, Yang W, Kannan Sivaraman K, Schembri LS, Gazdik M, Grin PM, Butler GS, Overall CM, Charman SA, McGowan S, Scammells PJ.
Abstract : Aminopeptidase N (APN/CD13) is a zinc-dependent M1 aminopeptidase that contributes to cancer progression by promoting angiogenesis, metastasis, and tumor invasion. We have previously identified hydroxamic acid-containing analogues that are potent inhibitors of the APN homologue from the malarial parasite Plasmodium falciparum M1 aminopeptidase (PfA-M1). Herein, we describe the rationale that underpins the repurposing of PfA-M1 inhibitors as novel APN inhibitors. A series of novel hydroxamic acid analogues were developed using a structure-based design approach and evaluated their inhibition activities against APN. N-(2-(Hydroxyamino)-2-oxo-1-(3',4',5'-trifluoro-[1,1'-biphenyl]-4-yl)ethyl)-4-(methylsulfonamido)benzamide (6ad) proved to be an extremely potent inhibitor of APN activity in vitro, selective against other zinc-dependent enzymes such as matrix metalloproteases, and possessed limited cytotoxicity against Ad293 cells and favorable physicochemical and metabolic stability properties. The combined results indicate that compound 6ad may be a useful lead for the development of anticancer agents.
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
13.6
%
|
|
SARS-CoV-2 3CL-Pro protease inhibition percentage at 20µM by FRET kind of response from peptide substrate
|
Severe acute respiratory syndrome coronavirus 2
|
4.92
%
|
|
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
|
-0.15
%
|
|
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
|
-0.31
%
|
|
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
|
-0.31
%
|
|
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
|
-0.15
%
|
|
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.
