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.

Previously we had shown that tripeptidyl trifluoromethyl ketones (TFMKs) possessing an N-terminal diarylacylsulfonamide, such as ICI 200,880 and ICI 200,355, displayed unparalleled protection against the lung damage induced by human neutrophil elastase (HNE) when the inhibitors were administered intratracheally. Since the diarylacylsulfonamides were designed specifically to afford a long residence time in the lung, it was not unexpected that inhibitors from this class of TFMKs were not active when administered orally. Upon evaluating a large number of peptidyl TFMKs possessing a variety of N-terminal groups, several compounds were identified which demonstrated oral activity. Compounds were evaluated for their oral activity by measuring their ability to inhibit the increase in lung weight relative to body weight (Lw/Bw), the increase in red blood cells, and the increase in white blood cells induced by intratracheally administered HNE (100 micrograms/hamster). A number of tripeptidyl trifluoromethyl ketones containing neutral N-terminal groups displayed good oral activity, while those containing basic, acidic, or polar groups did not. Compound 50, possessing an N-terminal 4-(CH3O)C6H4CO group, was particularly effective, reducing Lw/Bw by 77%, red cells by 89%, and white cells by 91% when dosed at 37.5 mg/kg orally. Thus, by modifying the N-terminal group of tripeptidyl TFMKs, inhibitors can be designed which are effective in vivo when administered either orally or intratracheally.

A novel series of human leukocyte elastase (HLE) inhibitors containing the beta-carbolinone ring system are reported. The design of these trifluoromethyl ketone-based inhibitors used a combination of structural information obtained from X-ray crystallography and molecular modeling investigations. The beta-carbolinone ring in these compounds serves as a highly efficient peptidiomimetic for the P2-P3 region of peptidyl trifluoromethyl ketone inhibitors of HLE. Several of the beta-carbolinones exhibit significant in vitro potency, with Ki values in the nanomolar range. Using aqueous molecular dynamics simulations, realistic models for the molecular recognition of these inhibitors by HLE have been obtained and are discussed. This series of compounds are found to have excellent selectivity for HLE over a number of other proteolytic enzymes, including closely related enzymes such as porcine pancreatic elastase.

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Background: GLY-200 is a non-absorbed polymer drug currently in Phase 2 clinical trials for the treatment of T2D. GLY-200 was designed to reversibly enhance the barrier properties of the intestinal mucus lining to non-invasively mimic gastric bypass and duodenal exclusion devices. In view of this mechanism of action, GLY-200 has the potential to interfere with the absorption of orally available drugs. As such, we investigated the effect of GLY-200 on the oral absorption of metformin, an antidiabetic agent commonly used in combination with other glucose-lowering medications. Methods: Metformin (100 mpk) was administered by oral gavage in saline to male Sprague Dawley rats (6-8 weeks old). GLY-200 (400 mpk) was dosed either simultaneously in the same gavage solution, or prior (1- or 3-hours) to the metformin dose. Blood samples were drawn at 0, 0.25, 0.5, 1, 2, 4, 7, 10, and 24 hours following the metformin dose, and a pharmacokinetic (PK) analysis was performed using a noncompartmental model (Phoenix WinNonlin v. 8.3). Results: GLY-200 altered the rate but did not meaningfully alter the extent of metformin absorption. The greatest effect was observed when the two drugs were dosed together (Cmax ↓34%; tmax ↑100%; AUC ↑11%). The observed changes may be a result of slowed GI transit with GLY-200 administration. Conclusions: The oral absorption and PK profile of metformin was not significantly altered when the drug was coadministered with GLY-200 or given 1- or 3-hours after a GLY-200 dose. These results suggest that GLY-200 could be used in combination with metformin, whose pharmacologic action is not dependent on Cmax. Disclosure M.Fineman: Employee; Glyscend Inc., Stock/Shareholder; Glyscend Inc. C.Bryant: Employee; Glyscend Inc. T.H.Jozefiak: Employee; Glyscend Inc., Stock/Shareholder; Glycologix, LLC. A.Nimgaonkar: Employee; Glyscend Inc. T.Carlson: Employee; Glyscend Inc.