P1' phenyl groups also provide potent, water-soluble MMP/TACE inhibitors on the succinate scaffold. Methoxyphenyl derivative 5 (PKF242-484) is a 0.6 nM inhibitor of human TACE with similar potency against MMP-1, -2, -3, -9, and -13 (34). Though ten-fold more potent than marimastat against purified enzyme, it is 20-fold more potent (IC50 = 48 nM) in human PBMCs. The analogous p-methylphenyl analog 6 is more than 5-fold less active against enzyme and in cells. A route for the synthesis of multi-kilogram quantities of 5 has been reported (35). In a murine LPS challenge model, a 10 mg/kg po dose of 5 reduced neutrophil and lymphocyte accumulation, and completely inhibited TNF-a levels, in bronchoalveolar lavage three hours post-LPS dose (36). It is also active in an ovalbumin-driven model of lung allergic inflammation.
Succinate hydroxamate 7 (Ro 32-7315), in which the amino residue of 3-5 was replaced with a sulfonyl hydrazide that bears a P2' isobutyl substituent, is a 5 nM inhibitor of the extracellular domain of TACE. Although 7 has sub-micromolar potencies in both THP-1 cells (IC50 = 350 nM) and rat whole blood (IC50 = 110 nM), a significant loss of activity is seen in HWB (IC50 = 2400 nM). It is 100-fold selective over MMP-1 and moderately selective (20 to 50-fold) over MMPs-2, -3, -7, -9, and -13, and non-selective against MMP-8 and MMP-12 (37). Compound 7 is active in suppressing LPS-stimulated TNF-a production in rats with an ED5o of 25 mg/kg po and gives statistically significant reductions in paw swelling, lesion score and joint mobility in a prophylactic rat AIA model at doses as low as 2.5 mg/kg ip bid. The ability of Ro 32-7315 to reduce LPS-induced TNF-a release in man was assessed in an ex vivo study. Blood sampled one hour after a single 450 mg oral dose of 7 affords a mean maximal 69% inhibition of TNF-a levels. The degree of inhibition correlates well with Ro 32-7315 plasma levels. A scaleable synthetic route to 7 has been reported (38).
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