Design and Synthesis of Carboxylate Inhibitors for Matrix Metalloproteinases.

Abstract

Matrix metalloproteinases (MMPs) are zinc endometallopeptidases that are involved in the degradation and remodeling of connective tissues. This family of enzymes shows proteolytic activity towards virtually all of the constituents of the extracellular matrix. The members of this family, currently numbering 20, can be classified into four groups, which are the collagenases that cleave triple-helical interstitial collagen; the gelatinases that cleave denatured collagen, elastin, and type IV and V collagen; the stromelysins that mainly cleave proteoglycans; and the membrane-type MMPs that have a C-terminal transmembrane domain for anchoring to the cell membrane. The MMPs are involved in crucial physiological and physiopathological events, such as wound healing, nerve growth, angiogenesis, and pregnancy. In these physiological processes, MMP activity is tightly regulated. [1][2][3][4][5] However, excessive MMP synthesis and release can lead to connective tissue degradation and destruction, which occurs in tumor invasion, metastasis, 6) corneal ulceration, 7) arthritis disease, 8a) periodontal disease, 9) and multiple sclerosis. 10) For example, increased levels of fibroblast collagenase (MMP-1) and stromelysin-1 (MMP-3) have been observed in the cartilage and synovium of patients with rheumatoid arthritis and osteoarthritis, and are correlated with the severity of the disease. 8b) Therefore, MMPs inhibitors may have a potent therapeutic effect on various proteolytic diseases.Many MMP inhibitors have been synthesized and developed. Several compounds are currently undergoing advanced clinical trials, such as batimastat (1), 11) marimastat (2), 12) trocade (3), 13) and AG3340 (4) 14) (Fig. 1). These inhibitors mimic the sequence of the substrate-cleavage site of MMPs and have hydroxamate as a zinc-chelating group (ZCG). This kind of design has been widely applied for other MMPs inhibitors.Previously, we also developed a series of peptidyl hydroxamates as MMP-1 inhibitors (Fig. 2), 15) our compounds mimicked the P 4 -P 1 substrate rather than the P 1 -P 1 Ј or P 1 -P 2 Ј sites in the above-mentioned MMP inhibitors (1)-(4). Inhibitors that mimic the P n Ј site have been studied extensively but little is known about P n site-mimicking inhibitors like our compounds because of their only modest inhibitory potency (IC 50 values in the order of 10 Ϫ6 M for MMP-1). However, we thought that this type of inhibitor could show further improvement of its inhibitory activity, since hydroxamate 15) and phosphorous 16) have been examined as ZCGs. Design Beside hydroxamate and phosphorous, the ZCGs utilized most frequently are thiol or carboxylate. The free thiols are unstable to oxidation in air at neutral pH during preparation and storage. 17) To avoid the disadvantage, we selected a carboxylate, which was expected to be relatively stable and to show good pharmacokinetics, as the ZCG. Although the carboxylate is a weaker ZCG than the others for MMP-1, 5) we designed the 2,3-diaminopropionic acid derivative (6) to compensate for thi...

Matrix Metalloproteinases in Venous Tissue Remodeling and Varicose Vein Formation

“…The IC 50 value for MMP-1 inhibition by carboxylates is in the μM range, i.e. 1000 fold less potent than the hydroxamate class [115,133]. Several carboxylate inhibitors have been developed to improve their MMP specificity.…”

Matrix Metalloproteinases as Potential Targets in the Venous Dilation Associated with Varicose Veins

“…The IC 50 for MMP-1 inhibition by carboxylates is in the μM range, i.e. 1000 fold less potent than hydroxamates [333, 372]. Several carboxylate inhibitors have been developed from the parent compound N(α)substituted 2,3-diaminoproprionic acid to improve their MMP specificity.…”

Design and Synthesis of Sulfur Based Inhibitors of Matrix Metalloproteinase-1.

“…The key intermediates (12), (16), (19) and (21) were prepared from Ntert-butyloxycarbonyl alanine (Boc-Ala-OH) (9). A mixed anhydride, which was prepared from the reaction of 9 with ethyl chloroformate (ClCO 2 Et)/Et 3 N, was reacted with excess diazomethane to give a diazomethyl ketone (10).…”

“…This was converted to the bromomethyl ketone (11) by reaction with HBr in ether. 16) The acetylsulfanylmethylketone (12) was obtained by reaction of 11 with potassium thioacetate followed by purification by silica gel column chromatography.…”

“…18) Then an addition of thioacetic acid to compound 15 was carried out under ultraviolet light catalyzed conditions 19) to afford 16. The acetylsulfanylethylketone (19) that differed from intermediate (12) by the distance between the carbonyl and mercapto groups, was prepared via the a,b-unsaturated compound (18). 20) Thus the aminoaldehyde (14) was transformed into the vinyl alcohol (17), which on Swern oxidation gave the corresponding a,b-unsaturated ketone (18).…”