Synthesis and Structure−Activity Relationship of α-Sulfonylhydroxamic Acids as Novel, Orally Active Matrix Metalloproteinase Inhibitors for the Treatment of Osteoarthritis

Abstract

The matrix metalloproteinases (MMPs) are a family of zinc-containing endopeptidases that play a key role in both physiological and pathological tissue degradation. These enzymes are strictly regulated by endogenous inhibitors such as tissue inhibitors of MMPs and alpha(2)-macroglobulins. Overexpression of these enzymes has been implicated in various pathological disorders such as arthritis, tumor metastasis, cardiovascular diseases, and multiple sclerosis. Developing effective small-molecule inhibitors to modulate MMP activity is one approach to treat these degenerative diseases. The present work focuses on the discovery and SAR of novel N-hydroxy-alpha-phenylsulfonylacetamide derivatives, which are potent, selective, and orally active MMP inhibitors.

Recent advances in MMP inhibitor design

“…The arguably underappreciated (in terms of its significance to MMP inhibitor design) observation of dual enantiomer recognition (now also observed with SB-3CT) may be direct evidence of the plasticity of the MMP active site with respect to substrate and inhibitor binding [18]. Complementary perspectives on this stereochemical issue are presented by Sani et al [83] (see also [80]) with their γ -trifluoromethyl-γ -sulfone MMP-3 inhibitors and by Pochetti et al [137] (vide infra, Fig. 10).…”

“…While both RS-130830 and 230954-09-3 are orally available, the shorter chain β-sulfonylhydroxamate class (exemplified by 239796-97-5 and SC-276) has improved ADME (especially metabolism) and MMP-1 selectivity properties. The phenoxyphenyl α-sulfonylpiperidinehydroxamate 239796-97-5 is an excellent MMP-9 and -13 inhibitor (IC 50 = 1 nM) that has a good TACE (IC 50 = 300 nM) sparing, and an excellent MMP-1 (IC 50 = 800 nM) sparing, profile [80,81]. It has excellent oral efficacy in an animal model of osteoarthritis (equal to or superior to RS-130830) [80,81].…”

“…The phenoxyphenyl α-sulfonylpiperidinehydroxamate 239796-97-5 is an excellent MMP-9 and -13 inhibitor (IC 50 = 1 nM) that has a good TACE (IC 50 = 300 nM) sparing, and an excellent MMP-1 (IC 50 = 800 nM) sparing, profile [80,81]. It has excellent oral efficacy in an animal model of osteoarthritis (equal to or superior to RS-130830) [80,81]. The thiophenoxyphenyl structure SC-276 has nearly identical sub-nanomolar K i values for MMP-2 and -13 inhibition as compared to its phenoxyphenyl cognate, and greatly improved MMP-1 sparing (SC-276 MMP-1 K i = 8700 nM, phenoxyphenyl cognate MMP-1 K i = 270 nM) [82].…”

Design, synthesis, and biological activity of novel, potent, and highly selective fused pyrimidine-2-carboxamide-4-one-based matrix metalloproteinase (MMP)-13 zinc-binding inhibitors

“…14,16 Therefore, inhibition of this enzyme is one of the most promising approaches for the treatment of cartilage degradation in arthritis. [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32] Recently, we described highly selective MMP-13 inhibitors, which do not bind the catalytic zinc ion ( Figure 1). [33][34][35][36] The inhibitors possess a pyrimidin-4-one-2-carboxamide core, which binds effectively to the primed regions (S1') of the catalytic active site 36,37 , and the fused pyrimidine carboxamide systems were successfully applied to other selective MMP-13 inhibitors.…”

Free Radicals and Biomarkers Related to the Diagnosis of Cardiorenal Syndrome

“…MMP are a large family of Ca 2+ -dependent zinc-containing endopeptidases that are responsible for tissue remodeling and degradation of extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. Overexpression of MMPs results in imbalance between its activity and the activity of TIMPs and can lead to a variety of disorders [145][146][147][148][149]. Since MMP plays a central role in organ development and subsequent tissue remodeling in inflammation and in injury, they are relevant HF biomarkers, especially in CRS [150].…”