Orally Active Trifluoromethyl Ketone Inhibitors of Human Leukocyte Elastase

Abstract

This paper describes the development a series of peptidyl trifluoromethyl ketone inhibitors of human leukocyte elastase which are found to have excellent pharmacological profiles. Methods have been developed that allow for the synthesis of these inhibitors in stereochemically pure form. Two of these compounds, 1k and 1l, have high levels of oral bioavailability in several species. Compound 1l has entered development as ZD8321 and is presently undergoing clinical evaluation. These compounds demonstrate that peptidyl trifluoromethyl ketone inhibitors can achieve high levels of oral activity and bioavailability, and therefore they may prove useful as therapeutic agents in the treatment of diseases in which elastase is implicated.

Biochemical and Pharmacological Characterization of 2-(9-(2-Piperidinoethoxy)-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yloxymethyl)-4-(1-methylethyl)-6-methoxy-1,2-benzisothiazol-3(2H)-one-1,1-dioxide (SSR69071), a Novel, Orally Active Elastase Inhibitor

“…The acute hemorrhagic assay conducted in the hamster is a widely used model for the assessment of in vivo activity of HLE inhibitors (Fletcher et al, 1990;Williams et al, 1991;Veale et al, 1997). This model is thought to be predictive for efficacy in emphysema (Fletcher et al, 1990).…”

“…The good oral activity of SSR69071 is very important because only a limited number of published elastase inhibitors show oral activity (Herbert et al, 1992;Metz and Peet, 1999;Skiles and Jeng, 1999;Leung et al, 2000) and their active doses are quite high, between 10 and 50 mg/kg (Herbert et al, 1992;Veale et al, 1997;Metz and Peet, 1999;Skiles and Jeng, 1999;Leung et al, 2000).…”

“…In the present study, we report on the biochemical and pharmacological properties of SSR69071. For comparison, (S)-1-[(S)-2-(methoxycarbonylamino)-3-methylbutyryl]-N-[(S)-2-methyl-1-(trifluoroacetyl)propyl]pyrrolidine-2-carboxamide (ZD8321), a selective and orally active elastase inhibitor (Veale et al, 1997), was synthesized and used as a reference in the biochemical and pharmacological studies (Fig. 1B).…”

The Dichotomy Between Understanding and Treating Emphysema

“…Sawyer and colleagues deposited the first high resolution crystal structure of porcine pancreatic elastase [21] into the protein data bank, and in 1982 Hughes and colleagues [22] solved a structure of the enzyme bound to a trifluoroacetyl dipeptide inhibitor (deposited in the PDB in 1986), thus making high resolution structures with and without bound ligand available to the research community. The trifluoroacetyl motif (shown in Figure 1) became a cornerstone of Zeneca's small molecule research program [23][24][25][26][27][28][29][30][31][32], which resulted in the clinical candidate ICI 200,880 [33]that was halted due to lack of efficacy in Phase II clinical trials. Fig.…”

A neutrophil elastase inhibitor reduces cigarette smoke-induced remodelling of lung vessels

“…These investigators used ZD0892, an orally active, selective, serine-elastase inhibitor, which is reasonably specific for neutrophil elastase although it inhibits other serine proteases, such as porcine pancreatic elastase, to a lesser extent [15]. ZD0892 also appears to be able to inhibit the endogenous vascular elastase expressed in monocrotaline-induced hypertension [13].…”