UK 370106

UK-370106 is a potent and highly selective MMP-3 (IC50 of 23 nM) and MMP-12 (IC50 of 42 nM) inhibitor with >1200-fold higher potency than MMP-1, MMP-2, MMP-9, and MMP-14, and about 100-fold than MMP-13 and MMP-8. UK-370106 potently inhibits cleavage of [3H]-fibronectin by MMP-3 (IC50 of 320 nM) and has little effect on keratinocyte migration in vitro[1][2].

Research Areas >> Inflammation/Immunology

Signaling Pathways >> Metabolic Enzyme/Protease >> MMP

MMP-3:23 nM (IC50)

MMP-12:42 nM (IC50)

MMP-8:1.75 μM (IC50)

MMP-13:2.3 μM (IC50)

MMP-7:5.8 μM (IC50)

MMP-9:30.4 μM (IC50)

MMP-2:34.2 μM (IC50)

MMP-14:66.9 μM (IC50)

The potency of UK-370106 (compound 7) for the inhibition of MMP-13 is 2.3 µM, some 100-fold less potent than its inhibition of MMP-3. UK-370106 is found to be inactive (IC50 > 100 µM) vs zinc metalloproteases PCP and TACE and possesses the following inhibitory potencies vs MMP-2 (IC50 of 34.2 µM), MMP-7 (IC50 of 5.8 µM), MMP-8 (IC50 of 1.75 µM), MMP-9 (IC50 of 30.4 µM) and MMP-14 (IC50 of 66.9 µM)[1]. UK-370106 potently inhibits cleavage of [3H]-fibronectin by MMP-3 (IC50 of 320 nM) but does not inhibit cleavage of [3H]-gelatin by either MMP-2 or -9 up to the highest concentration tested (100 µM)[1]. UK-370106 is not cytotoxic to, nor affected proliferation of, fibroblasts, keratinocytes, or endothelial cells at 50-100 µM in vitro[1].

Following iv (rat; 2 mg/kg) or topical administration to dermal wounds (rabbit), UK-370106 (compound 7) is cleared rapidly (t1/2 = 23 min) from plasma, but slowly (t1/2 approximately 3 days) from dermal tissue. In a model of chronic dermal ulcers, topical administration of UK-370106 for 6 days substantially inhibits MMP-3 ex vivo[1].

[1]. Fray MJ, et al. 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.

[2]. Whitlock GA, et al. A novel series of highly selective inhibitors of MMP-3. Bioorg Med Chem Lett. 2007 Dec 15;17(24):6750-3. Epub 2007 Oct 17.