Richard P. Dunlap

A benzisothiazolone class of potent, selective mechanism-based inhibitors of human leukocyte elastase

Abstract A new type of mechanism-based inhibitor of human leukocyte elastase (HLE) is described that are designed to inhibit HLE by a suicide route to form an inhibitor-enzyme complex by cross linking the enzyme active site. A mechanism of HLE inhibition is proposed and was used to design analogues with improved potency. The structure-activity relationships described in this paper are consistent with the proposed mechanism of HLE inhibition, and led to WIN 62785 ( 12 ), the most potent compound in this series with a K i * = 0.3 nM.

The design of potent and stable benzisothiazolone inhibitors of human leukocyte elastase

Abstract The lead compound for this SAR study, benzisothiazolone 1a, was a 15 nM inhibitor of HLE, but was unstable in human blood ( t 1 2 min). The introduction of lipophilic substituents at the R4-position such as ethyl or isopropyl and modulation of the electrophilicity of the benzisothiazolone carbonyl led to the identification of a potent ( K i ∗ =0.27 nM) and blood stable ( t 1 2 =260 min) inhibitor 2e, WIN 63395.

Alkoxy substituted benzisothiazolone (BIT) derivatives: potent inhibitors of human leukocyte elastase

Abstract Alkoxy substituted benzisothiazolones (BIT) are reported as inhibitors of human leukocyte elastase (HLE). Structure-activity relationship study results are described. The contribution of alkoxy substituents towards improving the stability of BIT derivatives in human blood is discussed. WIN 68769 ( 12 ) with a Ki ∗ = 0.022 nM is the most potent analog synthesized in this series.

Chapter 19. Biochemistry and Inhibition of Collagenase and Stromelysin

Publisher Summary Collagens and proteoglycans are the major organic molecules of cartilage and bone that are the primary endogenous substrate for the collagenases and an important substrate for stromelysin respectively. The collagenases and stromelysin are extracellular, calcium dependent, zinc endoproteinases whose substrates include the macromolecular components of the extracellular matrix. Of the approximately 10 human matrix metalloproteinases (MMPs) that have been tentatively identified to date, six have been isolated and have had their enzymatic activity studied: these are fibroblast collagenase (HFC or MMP-1), stromelysin (HFS or MMP-3), neutrophil collagenase (HNC or MMP-8), 72 kDa gelatinase (HFG or MMP-2), 92 kDdneutrophil gelatinase (HNG or MMP-9), and uterine metalloproteinase (PUMP-1 or MMP-7). This chapter discusses the biochemistry and inhibition of three of these enzymes: hybrid fiber-coaxia (HFC), HNC, and HFS. Substantial progress has occurred in the cloning, isolation, and purification of HFC and HFS in quantities sufficient for mechanistic and structural studies. Peptide-based assays have been developed that are much more accurate and reliable than assays based on the hydrolysis of biological macromolecules. Although potent, peptide-based inhibitors of HFC have been designed, studies of the activity in vivo have appeared. It is only when inhibitors with in vivo activity are obtained then the role of the MMPs in disorders, such as arthritis and peridontal disease, can be established.

Inhibitors of human leukocyte elastase. 2.1 synthesis and sar of benzisothiazolinylmethyl aryl ethers

Abstract A series of 4-isopropyl benzisothiazolinylmethyl aryl ethers were prepared and evaluated as inhibitors of human leukocyte elastase (HLE). Among the phenols attached as leaving groups onto N-methyl of the 4-isopropyl benzisothiazolone nucleus, the sulfonamido phenol 26 was found to be the best. Compound 7i with K i ∗ = 0.8 nM was the most potent inhibitor in this series.

Inhibitors of human leukocyte elastase. 3.1 inhibition by tetrahydrobenzisothiazolinylmethyl aryl carboxylates

Abstract Potent mechanism based inhibition of human leukocyte elastase (HLE) by tetrahydrobenzisothiazolones ( 2 ) is described. Structure activity relationships studies led to the identification of WIN 62816 ( 2c ), the most potent inhibitor in this series with a K i ∗ = 0.7 nM.

A comparative SAR and computer modeling study of benzisothiazolone, mechanism-based inhibitors with porcine pancreatic and human leukocyte elastase

Abstract Distinct differences in the SAR for HLE and PPE inhibition in this class of compounds were observed. For example, larger lipophilic substituents at the benzisothiazolone 4-position afforded inhibitors that were potent against HLE, but inactive against PPE. These findings are consistent with computer models of inhibitor-enzyme complexes built using the X-ray structure coordinates of HLE and PPE. These models show that substituents at the benzisothiazolone 4-position fit into the S1 specificity pocket of the enzyme and that other differences in the SAR can be explained based on the structural differences of HLE and PPE.