Albert J. Mura

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.

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.