Drug Insight: Tumor Necrosis Factor Converting Enzyme as a Pharmaceutical Target for Rheumatoid Arthritis

Marcia L Moss; Liora Sklair-Tavron; Raphael Nudelman


Nat Clin Pract Rheumatol. 2008;4(6):300 

In This Article

Chemistry of TACE Inhibition

TACE inhibitors were initially nonspecific and also targeted MMPs. For example, GSK's GW3333 (compound 1 in Table 2 , Figure 2) inhibits TACE, MMP1, MMP2, MMP3, MMP8, MMP9 and MMP13,[17,28] and was undergoing preclinical studies as an orally active therapy for RA. GSK stated that GW3333 was the first inhibitor with sufficient duration of action to chronically inhibit TACE and MMPs in the rat. The compound also has the potential to cause tendonitic adverse effects, however, as it is not selective for TACE over other MMPs, and also has low solubility in gastric fluid. The development of GW3333 and more recent orally available TACE-selective inhibitors[29] has been discontinued. The terminated studies include GSK's program for optimization of GW3333, in which GW4459 (compound 7 in Table 2 , Figure 2) was identified as a potent (IC50 = 4.3 nM) TACE inhibitor with selectivity over MMP1 and MMP3 and high solubility in gastric fluid,[30] and a study of another potent and selective orally available TACE inhibitor, which has 5-methyl-thienylalanine and threonine side chains in the reverse hydroxamate series.[29] Wyeth also was developing orally active, small-molecule inhibitors of TACE for the treatment of RA. TMI-1 (compound 2 in Table 2 , Figure 2) is one orally available, small-molecule dual inhibitor of TACE and MMPs that was developed.[18]

BMS-561392 (compound 3 in Table 2 , Figure 2) is an orally active, partially selective inhibitor of TACE.[19] It also targets MMP3 and MMP12 as well as ADAMTS4 (ADAM with thrombospondin motifs 4).[21] BMS-561392 is a gamma-lactam analog of the nonpeptide, small-molecule selective TACE inhibitor IK682.[31] In animal models, it functions as a DMARD. BMS-561392 originated at Dupont-Merck and was being developed by BMS. It was the first partially selective TACE inhibitor to reach phase II clinical trials for the treatment of RA and was tested in the preclinical setting for inflammatory bowel disease.

BMS has synthesized a series of structurally diverse TACE inhibitors as potential backup compounds to BMS-561392. At the 228th National Meeting of the American Chemical Society in 2004, BMS researchers announced the development of potent and selective TACE inhibitors from a series of β -benzamido hydroxamic acids.[32] The lead compound, DPC-A38088, demonstrated potent binding and a good pharmacokinetic profile in rats and dogs. Another TACE inhibitor, DPH-067517, was under development by BMS for the treatment of cerebral ischemia.[33] Duan et al. discovered a new series of TACE inhibitors by using a pyrimidine-2,4,6-trione as a hydroxamate replacement.[34] Even though pyrimidine-2,4,6-trione is a markedly weaker ligand for the zinc ion than is hydroxamic acid, highly potent TACE inhibitors have been identified through optimization of the rest of the molecule. The most potent compound reported (compound 8 in Table 2 , Figure 2) had an IC50 of 2 nM. Despite the success of BMS in producing selective TACE inhibitors with drug-like properties, their program, including the development of BMS-561392, has been discontinued because of concerns over mechanism-based liver toxicity.

Several elegant structure-based methods and structure-activity relationship optimization programs have generated new potent, selective and orally bioavailable TACE inhibitors. These agents include piperidine β-sulfone hydroxamates (Wyeth)[35] and β-benzamido hydroxamic acids (BMS).[36] These compounds are at very early stages of preclinical studies.

The most recent partially selective TACE inhibitor to advance into the clinic was TMI-005 (detailed in text above);[20] however, its development has been discontinued, in part owing to lack of efficacy. Other companies have produced TACE inhibitors that have subsequently been discontinued; for example, Hoffmann-La Roche (R-618), UCB (CH-138), and Wakanuga Pharmaceutical Co.[37] (W-3646; compound 9 in Table 2 , Figure 2). Some companies, however, are running programs that are still considered to include active TACE inhibitors, such as those operated by Vertex[38] (thiol-based TACE inhibitors [e.g. compound 10 in Table 2 , Figure 2]) and Wyeth. Bayer Schering Pharma has filed several patent applications with very broad claims that indicate their activity in this field (WO2005/121130, US2006/0178366, US2006/0252778, US2007/0167426).

One of the main hurdles to overcome in chemistry programs is the issue of why low nanomolar inhibitors of TACE don't necessarily translate to inhibitors with good activity in cells and human whole blood. This discrepancy is thought to arise because inhibitors need to penetrate through or into the cell membrane to inhibit TACE. In complex systems, such as cell-based assays, competition for the inhibitor might occur following protein binding.


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