Target Validation Information
TTD ID T68251
Target Name Matrix metalloproteinase-2 (MMP-2)
Type of Target
Successful
Drug Potency against Target BB-3644 Drug Info IC50 = 80 nM [24]
BMS 275291 Drug Info IC50 = 39 nM [23]
Marimastat Drug Info Ki = 6 nM [25]
PG-530742 Drug Info Complete Inhibition = 150 ng/mL [21]
Tanomastat Drug Info Ki = 11 nM [22]
(+/-)5-(biphenyl-4-yl)-3-hydroxypentanoic acid Drug Info IC50 = 4520 nM [16]
2-(4'-chloro-biphenyl-4-sulfonyl)-pentanoic acid Drug Info IC50 = 792 nM [11]
2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide Drug Info IC50 = 1300 nM [18]
3-(4-(2-phenylethynyl)benzoyl)pentanoic acid Drug Info IC50 = 440 nM [8]
3-(4-Phenylethynylbenzoyl)nonanoic acid Drug Info IC50 = 1660 nM [8]
4-(4-(dec-1-ynyl)phenyl)-4-oxobutanoic acid Drug Info IC50 = 3070 nM [8]
5-(4-Phenoxy-phenyl)-pyrimidine-2,4,6-trione Drug Info IC50 = 9000 nM [3]
5-Biphenyl-4-yl-5-ethyl-pyrimidine-2,4,6-trione Drug Info IC50 = 898 nM [3]
5-Biphenyl-4-yl-5-hexyl-pyrimidine-2,4,6-trione Drug Info IC50 = 868 nM [3]
5-Hexyl-5-phenyl-pyrimidine-2,4,6-trione Drug Info IC50 = 1300 nM [3]
BB-1101 Drug Info IC50 = 1.8 nM [19]
CIPEMASTAT Drug Info Ki = 154 nM [2]
CIPEMASTAT Drug Info IC50 = 7 nM
Cis-2-aminocyclohexylcarbamoylphosphonic acid Drug Info IC50 = 4000 nM [13]
Clinopodic acid C Drug Info IC50 = 3260 nM [17]
Epigallocatechin gallate Drug Info IC50 = 9600 nM [15]
GM6001 Drug Info IC50 = 0.4 nM [14]
IK-862 Drug Info Ki = 2050 nM [4]
L-696418 Drug Info Ki = 200 nM
Lithospermic acid Drug Info IC50 = 10200 nM [17]
MMI270 Drug Info IC50 = 15 nM [1]
N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide Drug Info IC50 = 1200 nM [18]
N-hydroxy-3-(2-oxo-2H-chromen-3-yl)propanamide Drug Info IC50 = 200 nM [12]
N-hydroxy-3-(6-methoxy-2-oxo-2H-chromen-3-yl) Drug Info IC50 = 590 nM [12]
PD-169469 Drug Info IC50 = 4 nM [9]
PNU-107859 Drug Info Ki = 3000 nM [6]
Ro-37-9790 Drug Info IC50 = 4.9 nM
RS-130830 Drug Info Ki = 0.22 nM [7]
SC-44463 Drug Info IC50 = 6 nM [5]
SR-973 Drug Info Ki = 7 nM [10]
UK-356618 Drug Info IC50 = 1790 nM [5]
[2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid Drug Info IC50 = 510 nM [18]
Action against Disease Model Neovastat Drug Info Neovastat has a marked inhibitory effect on the formation of blood vessels in the chicken embryo vascularization assay (EVT) and endothelial cell proliferation. In vivo experiments showed that oral administration of Neovastat blocks the formation of blood vessels in Matrigel implants containing basic fibroblast growth factor (bFGF). The antiangiogenic activity of Neovastat was found to be associated with two mechanisms of action. In addition to the inhibition of the matrix metalloproteinase activities (MMP-2, MMP-9, and MMP-12), Neovastat inhibits vascular endothelial growth factor (VEGF) binding to endothelial cells, VEGF-dependent tyrosine phosphorylation, and VEGF-induced vascular permeability in mice. Neovastat was also found to have a significant antit uMor activity. Oral administration of Neovastat in mice with subcutaneous grafted breast cancer (DA3) cells showed a significant reduction in t uMor vol uMe. Neovastat also decreased the n uMber of lung metastases in the Lewis lung carcinoma model. [20]
References
REF 1 Picking the S1, S1' and S2' pockets of matrix metalloproteinases. A niche for potent acyclic sulfonamide inhibitors. Bioorg Med Chem Lett. 1999 Jun 21;9(12):1691-6.
REF 2 Protease inhibitors: current status and future prospects. J Med Chem. 2000 Feb 10;43(3):305-41.
REF 3 Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors. Bioorg Med Chem Lett. 2001 Apr 23;11(8):969-72.
REF 4 Discovery of gamma-lactam hydroxamic acids as selective inhibitors of tumor necrosis factor alpha converting enzyme: design, synthesis, and structu... J Med Chem. 2002 Nov 7;45(23):4954-7.
REF 5 A potent, selective inhibitor of matrix metalloproteinase-3 for the topical treatment of chronic dermal ulcers. J Med Chem. 2003 Jul 31;46(16):3514-25.
REF 6 A molecular basis for the selectivity of thiadiazole urea inhibitors with stromelysin-1 and gelatinase-A from generalized born molecular dynamics s... J Med Chem. 2004 Jun 3;47(12):3065-74.
REF 7 Structure-based design of potent and selective inhibitors of collagenase-3 (MMP-13). Bioorg Med Chem Lett. 2005 Feb 15;15(4):1101-6.
REF 8 Selective inhibition of matrix metalloproteinase isozymes and in vivo protection against emphysema by substituted gamma-keto carboxylic acids. J Med Chem. 2006 Jan 26;49(2):456-8.
REF 9 Structural insight into the stereoselective inhibition of MMP-8 by enantiomeric sulfonamide phosphonates. J Med Chem. 2006 Feb 9;49(3):923-31.
REF 10 Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors. Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63.
REF 11 Synthesis and SAR of alpha-sulfonylcarboxylic acids as potent matrix metalloproteinase inhibitors. Bioorg Med Chem Lett. 2006 Jun 15;16(12):3096-100.
REF 12 Chromen-based TNF-alpha converting enzyme (TACE) inhibitors: design, synthesis, and biological evaluation. Bioorg Med Chem. 2008 Jan 1;16(1):530-5.
REF 13 Carbamoylphosphonate matrix metalloproteinase inhibitors 6: cis-2-aminocyclohexylcarbamoylphosphonic acid, a novel orally active antimetastatic mat... J Med Chem. 2008 Mar 13;51(5):1406-14.
REF 14 Introduction of the 4-(4-bromophenyl)benzenesulfonyl group to hydrazide analogs of Ilomastat leads to potent gelatinase B (MMP-9) inhibitors with i... Bioorg Med Chem. 2008 Sep 15;16(18):8745-59.
REF 15 Regioselective synthesis of methylated epigallocatechin gallate via nitrobenzenesulfonyl (Ns) protecting group. Bioorg Med Chem Lett. 2009 Aug 1;19(15):4171-4.
REF 16 The identification of beta-hydroxy carboxylic acids as selective MMP-12 inhibitors. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5760-3.
REF 17 Matrix metalloproteinase-2 inhibitors from Clinopodium chinense var. parviflorum. J Nat Prod. 2009 Aug;72(8):1379-84.
REF 18 Design, synthesis, biological evaluation, and NMR studies of a new series of arylsulfones as selective and potent matrix metalloproteinase-12 inhib... J Med Chem. 2009 Oct 22;52(20):6347-61.
REF 19 Broad spectrum matrix metalloproteinase inhibitors: an examination of succinamide hydroxamate inhibitors with P1 C alpha gem-disubstitution. Bioorg Med Chem Lett. 1998 Jun 16;8(12):1443-8.
REF 20 Neovastat, a naturally occurring multifunctional antiangiogenic drug, in phase III clinical trials. Semin Oncol. 2001 Dec;28(6):620-5.
REF 21 Selective matrix metalloproteinase inhibition attenuates progression of left ventricular dysfunction and remodeling in dogs with chronic heart fail... Am J Physiol Heart Circ Physiol. 2006 Jun;290(6):H2522-7.
REF 22 BAY 12-9566, a novel inhibitor of matrix metalloproteinases with antiangiogenic activity. Clin Cancer Res. 1999 Nov;5(11):3603-7.
REF 23 Inhibition of angiogenesis and metastasis in two murine models by the matrix metalloproteinase inhibitor, BMS-275291. Cancer Res. 2001 Dec 1;61(23):8480-5.
REF 24 Recent developments in the design of specific Matrix Metalloproteinase inhibitors aided by structural and computational studies. Curr Pharm Des. 2005;11(3):295-322.
REF 25 BCL-2 family antagonists for cancer therapy. Nat Rev Drug Discov. 2008 Dec;7(12):989-1000.

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