MMP-13 antagonist | BI-4394

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Target protein: 
MMP-13
Probe Name: 
BI-4394
MOLECULAR WEIGHT [DA]: 
446.5
In stock: 
116

Chemical structure

Highlights

BI-4394 is a highly potent inhibitor of MMP-13 (IC50 = 1 nM) with excellent (>1000 fold) selectivity against several other metalloproteinases and is thus a high quality tool compound for testing biological hypotheses involving this target.

 

According to the UK Third Generation Cannabinoid Act, the molecule cannot be shipped to the United Kingdom.

 

 

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Target information

Matrix metalloproteinases (MMPs) are zinc- and calcium-dependent peptidases, involved in the cleavage of collagen, gelatin and other proteins in the extracellular matrix and tissue remodelling. There are approximately 23 known human MMPs that are grouped into subtypes based on their substrates. MMPs have a conserved active site motif where a tris(histidine)-bound zinc(II) acts as the catalytic site for substrate hydrolysis. MMP-13 (also known as collagenase 3, CLG3) is the most efficient enzyme of this class at degrading collagen II, the committed step in articular cartilage degradation and progressive joint damage associated with rheumatoid arthritis (RA). Broad-spectrum MMP inhibitors have failed in clinical trials at least in part due to a joint-stiffening side effect, termed musculoskeletal syndrome (MSS). This was likely due to inhibition of MMPs other than MMP-13 and high selectivity for MMP-13 over other MMPs is therefore favourable.

BI-4394 bound to MMP13, as observed by X-ray crystallography (PDB code: 5BPA)

BI-4394 bound to MMP-13, as observed by X-ray crystallography (PDB code: 5BPA)

In vitro Activity

BI-4394 is a potent inhibitor of MMP-13 with an IC50 value of 1 nM.

Probe name / Negative control

BI-4394

BI-4395

MW [Da]

446.5

374.4

Inhibition of MMP-13 (IC50) [nM]

1

>26,000

Inhibition of bovine nasal cartilage with human full length MMP-13 (IC50) [nM]

31

n.d.

In vitro DMPK parameters

Probe name / Negative control

BI-4394

BI-4395

logP (pH 2)

1.9

n.d.

Solubility @ pH 7.4 [µg/ml]

60

>96 (pH 7)

Solubility @ pH 4 [µg/ml]

<0.1

<0.1

CACO permeability @ pH 7.4 [*10-6 cm/s]

0.6

n.d.

CACO efflux ratio

27

n.d.

Microsomal stability (human/rat) [% QH]

40

41

25

n.d.

Plasma protein binding (human) [%]

98

n.d.

In vivo DMPK parameters

BI-4394

RAT

Clearance [ml/(min*kg)]b

39

Mean residence time after iv dose [h]

0.5

F [%]

39

Vss [l/kg]

0.4

biv dose: 1 mg/kg

Negative control

MOLECULAR WEIGHT OF NEGATIVE CONTROL [DA]: 
374.4

BI-4395  which serves as a negative control

BI-4395 which serves as a negative control

Selectivity

BI-4394 is highly (>1000 fold) selective against other matrix metalloproteinases (MMP-1, 2, 3, 7, 8, 9, 10, 12, 14):

MMP

1

2

3

7

8

9

10

12

13

14

IC50 [µM]

>22

18

>22

>22

>22

8.9

16

>22

0.001

8.3

BI-4394

Selectivity data available

Cerep®

Yes

Panlabs®

No

Invitrogen®

Yes

DiscoverX®

No

Dundee

No

Invitrogen:
18/56 kinases hit >50 inhibition at 10 µM: STK6 (99%), MAPKAPK2 (99%), RPS6KA3 (95%), MAPK14 (94%), GSK3B (94%), AMPK A1B1G1 (92%), PRKACA (90%), PIM1 (86%), KDR (83%), AKT1 (76%), SRC (75%), DYRK3 (72%), MAP4K4 (68%), MET (57%), JAK3 (56%), IKBKB (52%), ABL1 (52%), NEK1 (51%).

Selectivity data can be downloaded free of charge here.

Download selectivity data: 

Co-crystal structure of the BI probe compound and the target protein

X-Ray co-crystal structure of BI-4394 bound to MMP-13 is available (see Figure "BI-4394 bound to MMP-13, as observed by X-ray crystallography (PDB code: 5BPA)", PDB code: 5BPA).

Summary

BI-4394 is a potent and highly selective inhibitor of MMP-13 that can be used as tool compound to test biological hypotheses in vitro.

According to the UK Third Generation Cannabinoid Act, the molecule cannot be shipped to the United Kingdom.

Supplementary data

References

  1. Matrix Metalloproteinases as Modulators of Inflammation and Innate Immunity

    Parks W. C., Wilson C. L., López-Boado Y. S.

    Nature Reviews Immunology 2004, 4, 617.

  2. Fragment-Based Discovery of Indole Inhibitors of Matrix Metalloproteinase-13

    Taylor S. J., Abeywardane A., Liang S., Muegge I., Padyana A. K., Xiong Z., Hill-Drzewi M., Farmer B., Li X., Collins B., Li J. X., Heim-Riether A., Proudfoot J., Zhang Q., Goldberg D., Zuvela-Jelaska L., Zaher H., Li J., Farrow N. A.

    J. Med. Chem. 2011, 54, 8174.

  3. Improving potency and selectivity of a new class of non-Zn-chelating MMP-13 inhibitors

    Heim-Riether A, Taylor S. J., Liang S., Gao D. A., Xiong Z., Michael August E., Collins B. K., Farmer B. T. 2nd, Haverty K., Hill-Drzewi M., Junker H. D., Mariana Margarit S., Moss N., Neumann T., Proudfoot J. R., Keenan L. S., Sekul R., Zhang Q., Li J., Farrow N. A.

    Bioorg. Med. Chem. Lett. 2009, 19, 5321.

  4. SAR studies of non-zinc-chelating MMP-13 inhibitors: Improving selectivity and metabolic stability

    Gao D.A., Xiong Z., Heim-Riether A., Amodeo L., August E. M., Cao X., Ciccarelli L., Collins B. K., Harrington K., Haverty K., Hill-Drzewi M., Li X., Liang S., Margarit S.M., Moss N., Nagaraja N., Proudfoot J., Roman R., Schlyer S., Keenan L.S., Taylor S., Wellenzohn B., Wiedenmayer D., Li J., Farrow N. A.

    Bioorg. Med. Chem. Lett. 2010, 20, 5039.

  5. Discovery of N-(4-Fluoro-3-methoxybenzyl)-6-(2-(((2S,5R)- 5-(hydroxymethyl)-1,4-dioxan-2-yl)methyl)-2H-tetrazol-5-yl)-2-methylpyrimidine-4-carboxamide. A Highly Selective and Orally Bioavailable Matrix Metalloproteinase-13 Inhibitor for the Potential Trea

    Ruminski P. G., Massa M., Strohbach J., Hanau C. E., Schmidt M., Scholten J. A., Fletcher T. R., Hamper B. C., Carroll J. N., Shieh H. S., Caspers N., Collins B., Grapperhaus M., Palmquist K. E., Collins J., Baldus J. E., Hitchcock J., Kleine H. P., Rogers M. D., McDonald J., Munie G. E., Messing D. M., Portolan S., Whiteley L. O., Sunyer T., Schnute M. E.

    J. Med. Chem. 2016, 59, 313.

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