Target Validation Information
TTD ID T34296
Target Name Matrix metalloproteinase-13 (MMP-13)
Type of Target
Clinical trial
Drug Potency against Target Marimastat Drug Info IC50 = 2 nM [19]
PG-530742 Drug Info Complete Inhibition = 150 ng/mL [18]
(+/-)5-(biphenyl-4-yl)-3-hydroxypentanoic acid Drug Info IC50 = 12000 nM [15]
1-(4-Methoxy-benzenesulfonyl)-heptane-3-thiol Drug Info IC50 = 45 nM [1]
2-(2-(biphenyl-4-yl)ethylsulfonyl)acetic acid Drug Info IC50 = 11300 nM [15]
2-(4-methoxybenzylthio)-6-methylpyrimidin-4-ol Drug Info IC50 = 1600 nM [13]
2-(biphenyl-4-ylsulfonamido)pentanedioic acid Drug Info IC50 = 280 nM [13]
2-(Biphenyl-4-ylsulfonyl)N-hydroxybenzamide Drug Info IC50 = 1400 nM [16]
3-(4-Methoxy-benzenesulfonyl)-cyclohexanethiol Drug Info IC50 = 22 nM [2]
3-(4-Methoxy-benzenesulfonyl)-cyclopentanethiol Drug Info IC50 = 500 nM [2]
3-(4-Methoxy-benzenesulfonyl)-hexane-1-thiol Drug Info IC50 = 6 nM [1]
3-(4-Methoxy-benzenesulfonyl)-pentane-1-thiol Drug Info IC50 = 4 nM [1]
3-(4-Methoxy-benzenesulfonyl)-propane-1-thiol Drug Info IC50 = 50 nM [1]
3-(4-Phenoxy-benzenesulfonyl)-cyclohexanethiol Drug Info IC50 = 1 nM [2]
3-(4-Phenoxy-benzenesulfonyl)-propane-1-thiol Drug Info IC50 = 0.5 nM [1]
3-Benzenesulfonyl-heptanoic acid hydroxyamide Drug Info IC50 = 18 nM [3]
3-Cyclohexanesulfonyl-heptanoic acid hydroxyamide Drug Info IC50 = 100 nM [3]
4-(2,2'-bithiophen-5-ylmethyleneamino)phenol Drug Info IC50 = 1700 nM [12]
4-(4-Methoxy-benzenesulfonyl)-butane-2-thiol Drug Info IC50 = 32 nM [1]
4-(methyl(4-phenylthiazol-2-yl)amino)phenol Drug Info IC50 = 13300 nM [12]
4-amino-3-(4-(hexyloxy)phenyl)-4-oxobutanoic acid Drug Info IC50 = 1300 nM [13]
5-(4'-cyanobiphenyl-4-yl)-3-hydroxypentanoic acid Drug Info IC50 = 2450 nM [15]
Apratastat Drug Info IC50 = 8 nM [8]
CIPEMASTAT Drug Info IC50 = 7 nM
CIPEMASTAT Drug Info Ki = 1 nM [10]
Curcumin Drug Info IC50 = 10300 nM [12]
Ethyl 2-cyano-2-(quinoxalin-2(1H)-ylidene)acetate Drug Info IC50 = 3400 nM [12]
GM6001 Drug Info IC50 = 5.2 nM [11]
IK-862 Drug Info Ki = 1417 nM [5]
MMI270 Drug Info IC50 = 4.3 nM [4]
N-Hydroxy-2-(4-phenoxy-benzenesulfonyl)benzamide Drug Info IC50 = 2700 nM [16]
N1,N3-bis(3-methoxybenzyl)isophthalamide Drug Info IC50 = 1350 nM [17]
N4,N6-dibenzylpyrimidine-4,6-dicarboxamide Drug Info IC50 = 400 nM [14]
PKF-242-484 Drug Info Ki = 0.5 nM [10]
Ro-37-9790 Drug Info IC50 = 4.9 nM
RS-130830 Drug Info Ki = 0.52 nM [7]
SR-973 Drug Info Ki = 10 nM [9]
UK-356618 Drug Info IC50 = 73 nM [6]
[2-(Biphenyl-4-sulfonyl)phenyl]acetic Acid Drug Info IC50 = 260 nM [16]
Action against Disease Model PG-530742 Drug Info MMP13 inhibitors have often been tested in explanted bovine nasal cartilage cultures, where the degradation of the cartilage explant is induced by adding the strong stimulus of a combination of interleukin-1a plus Oncostatin M, which induces both MMP1 and MMP13. MMP13 inhibitor could block cartilage degradation in this culture system, but its potency was fairly weak relativeto its in vitro enzyme inhibition potency. MMP13 inhibitors showed significant protection of cartilage as evaluated by examination of the gross structure of the cartilage surface. [20]
References
REF 1 Discovery of a novel series of selective MMP inhibitors: identification of the gamma-sulfone-thiols. Bioorg Med Chem Lett. 1999 Apr 5;9(7):943-8.
REF 2 Synthesis and identification of conformationally constrained selective MMP inhibitors. Bioorg Med Chem Lett. 1999 Jul 5;9(13):1757-60.
REF 3 Hydroxamic acid derivatives as potent peptide deformylase inhibitors and antibacterial agents. J Med Chem. 2000 Jun 15;43(12):2324-31.
REF 4 Heterocycle-based MMP inhibitors with P2' substituents. Bioorg Med Chem Lett. 2001 Apr 23;11(8):1009-13.
REF 5 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 6 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 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 Acetylenic TACE inhibitors. Part 3: Thiomorpholine sulfonamide hydroxamates. Bioorg Med Chem Lett. 2006 Mar 15;16(6):1605-9.
REF 9 Synthesis and evaluation of succinoyl-caprolactam gamma-secretase inhibitors. Bioorg Med Chem Lett. 2006 May 1;16(9):2357-63.
REF 10 A cassette-dosing approach for improvement of oral bioavailability of dual TACE/MMP inhibitors. Bioorg Med Chem Lett. 2006 May 15;16(10):2632-6.
REF 11 Discovery and characterization of a novel inhibitor of matrix metalloprotease-13 that reduces cartilage damage in vivo without joint fibroplasia si... J Biol Chem. 2007 Sep 21;282(38):27781-91.
REF 12 High throughput screening of potentially selective MMP-13 exosite inhibitors utilizing a triple-helical FRET substrate. Bioorg Med Chem. 2009 Feb 1;17(3):990-1005.
REF 13 Ranking the selectivity of PubChem screening hits by activity-based protein profiling: MMP13 as a case study. Bioorg Med Chem. 2009 Feb 1;17(3):1101-8.
REF 14 Calculation of binding free energies for non-zinc chelating pyrimidine dicarboxamide inhibitors with MMP-13. Bioorg Med Chem Lett. 2009 Jan 1;19(1):47-50.
REF 15 The identification of beta-hydroxy carboxylic acids as selective MMP-12 inhibitors. Bioorg Med Chem Lett. 2009 Oct 1;19(19):5760-3.
REF 16 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 17 Discovery of (pyridin-4-yl)-2H-tetrazole as a novel scaffold to identify highly selective matrix metalloproteinase-13 inhibitors for the treatment ... Bioorg Med Chem Lett. 2010 Jan 15;20(2):576-80.
REF 18 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 19 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 20 Selective MMP13 inhibitors. Med Res Rev. 2011 Nov;31(6):863-94.

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