Jeffrey B. Epp

Potent and specific inhibition of human leukocyte elastase, cathepsin G and proteinase 3 by sulfone derivatives employing the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold.

This paper describes the results of structure-activity relationship studies in a series of heterocyclic mechanism-based inhibitors based on the 1,2,5-thiadiazolidin-3-one 1,1 dioxide scaffold I and capable of interacting with the Sn and Sn subsites of a serine proteinase. Sulfone derivatives of I were found to be highly effective, time-dependent inhibitors of human leukocyte elastase (HLE), cathepsin G (Cat G) and proteinase 3 (PR 3). The judicious selection of an R1 group (accommodated at the primary specificity site S1) that is based on the known substrate specificity of a target serine proteinase, was found to yield highly selective inhibitors. The presence of a benzyl group (R2 = benzyl) at the S2 subsite was found to lead to a pronounced enhancement in inhibitory potency. Furthermore, the effective use of computer graphics and modeling has led to the design of potent, water-soluble inhibitors. The results of these studies demonstrate that the 1,2,5-thiadiazolidin-3-one 1,1, dioxide platform provides an effective means for appending recognition elements in a well-defined vector relationship, and in fashioning highly-selective and potent inhibitors of serine proteinases.

Design, synthesis, and in vitro inhibitory activity toward human leukocyte elastase, cathepsin G, and proteinase 3 of saccharin-derived sulfones and congeners

The inhibitory activity toward human leukocyte elastase (HLE), cathepsin G (Cat G), and proteinase 3 (PR 3) of a series of saccharin derivatives having a sulfinate leaving group was investigated. The results of this study revealed that (a) inhibitory activity is dependent on the nature and pKa of the leaving group, and (b) the synthesized saccharin derivatives exhibit selective inhibition toward HLE and PR 3, with low or no activity toward cathepsin G. The results of exploratory biochemical, HPLC and high-field 13C NMR studies are also described.

Isoxazoline derivatives as potential inhibitors of the proteolytic enzymes human leukocyte elastase, cathepsin G and proteinase 3: a structure-activity relationship study.

Abstract A series of isoxazoline derivatives were synthesized and investigated for their in vitro inhibitory activity towards human leukocyte elastase, cathepsin G and proteinase 3.

Inhibitors of human neutrophil cathepsin G : structural and biochemical studies

The interaction of a series of sulfonate and phosphate esters derived from N-hydroxysuccinimide with human leukocyte cathepsin G was investigated. The synthesized compounds were found to be time-dependent inhibitors of the enzyme. The composite interplay of steric and electronic effects leads to the formation of acyl enzymes of variable stability, ultimately resulting in partial or full recovery of enzymatic activity. Compounds acting via phosphorylation of the active site serine inactivated the enzyme rapidly and irreversibly.

Design, synthesis and biological evaluation of succinimide derivatives as potential mechanism-based inhibitors of human leukocyte elastase, cathepsin G and proteinase 3

Structure-activity relationship study and in vitro biochemical studies with human leukocyte elastase, cathepsin G and proteinase 3 were conducted using a series of succinimide derivatives.

Dual-action inhibitors of proteolytic enzymes: potential therapeutic agents for cystic fibrosis and related ailments

Abstract The design, synthesis and in vitro inhibitory activity toward human leukocyte elastase of a series of dual action saccharin derivatives are described.

Potential mechanism-based inhibitors of proteolytic enzymes

Abstract The design, synthesis, and inhibitory activity toward human neutropil elastase, of a series of potential mechanims-based inhibitors is described. The design, synthesis, and inhibitory activity toward human neutrophile elastase, of a series of potential mechanism-based inhibitors (I-III) is described.

Mechanism-based inhibition of human leukocyte elastase and cathepsin G by susbtituted dihydrouracils

A series of dihydrouracil derivatives has been synthesized and investigated for their in vitro inhibitory activity toward human leukocyte elastase (HLE) and cathepsin G (Cath G). Alkyl [sulfonyl(oxy)] uracils 1-2 were found to be efficient, time-dependent inhibitors of elastase (kobs/[I] M-1 s-1 values ranged between 480 and 8110). These compounds formed acyl enzymes that exhibited variable hydrolytic stability which appeared to be dependent on the nature of the R1 group (believed to be accommodated at the primary specificity site, S1). The acyl enzymes formed with cathepsin G deacylated rapidly, leading to a significant regain of enzymatic activity. In sharp contrast, the corresponding phosphorus compounds 3-4 were found to be potent, time-dependent irreversible inhibitors of HLE. Furthermore, the results of the structure-activity relationship studies suggest that the binding modes of compounds 1-2 and 3-4 may be different.

3-(Alkylthio)-N-hydroxysuccinimide derivatives: potent inhibitors of human leukocyte elastase

A series of 3-(alkylthio)-N-hydroxysuccinimide derivatives was synthesized and their inhibitory activity towards human leukocyte elastase (HLE) was investigated. The interaction of the compounds having a 3-alkylthioether side chain (compounds 1 and 2) with HLE was found to involve rapid acylation of the enzyme, followed by total regain of enzymatic activity within 3 h. Interestingly, compounds 3-8, having an oxidized thioether side chain, were found to be highly effective, time-dependent, irreversible inhibitors of the enzyme. The k(obs)/I values for compounds 3-8 ranged between 890 and 24,000 M-1 s-1. These findings demonstrate that, unlike the physiological inhibitor of HLE (alpha-1-proteinase inhibitor), which is inactivated upon oxidation, low-molecular-weight compounds retain and/or show enhanced inhibitory activity towards HLE upon oxidation of the thioether side chain and lay the groundwork for the development of compounds that embody proteinase inhibitory and antioxidant activity.

The Gabriel-Colman rearrangement in biological systems: design, synthesis and biological evaluation of phthalimide and saccharin derivatives as potential mechanism-based inhibitors of human leukocyte elastase, cathepsin G and proteinase 3

The results of a structure-activity relationship study focusing on the interaction of a series of phthalimide and saccharin derivatives with leukocyte elastase, cathepsin G and proteinase 3 are described. The phthalimide derivatives were found to be inactive while some of the saccharin derivatives were found to be fair inhibitors of these enzymes.