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• W2263458534 abstract "C227 Clinical development of orally bioavailable proteasome inhibitors offers improvement in both dosing flexibility and patience convenience over intravenous (IV) administration. Currently, clinical application of proteasome inhibitors utilizes compounds that are administered IV six or more times per month. Frequent IV administration can result in significant impact on patient quality of life and can result in increased complications from therapy, such as injection site reactions. We undertook a medicinal chemistry effort to generate structural analogs of carfilzomib, a tetrapeptide epoxyketone proteasome inhibitor currently in phase II clinical studies for multiple myeloma, with the intent of developing an orally administered proteasome inhibitor for the treatment of malignant diseases. Over 200 compounds were screened in mice for pharmacodynamic (PD) activity by measuring proteasome inhibition in blood and tissues following oral (PO) administration and 44 of them, all tripeptides, were found to induce significant (>40%) inhibition of proteasome activity. Structure activity relationship (SAR) analysis of these data showed that both leucine (Leu) and phenylalanine (Phe) at the P1 position are tolerated and that the addition of serine methyl ether [Ser(Me)] residues at either the P2 or the P3 position dramatically improved oral bioavailability over the hydrophobic residues contained in carfilzomib at the same positions. In parallel, compounds were also tested in vitro for solubility, intestinal cell permeability, liver microsomal metabolism and sensitivity to efflux pumps in order to determine which properties were associated with oral bioavailability. A subset of the most potent molecules (as measured by proteasome inhibition following PO administration) was tested further in mice and rats for absolute bioavailability, dose dependent proteasome inhibition, toxicity and anti-tumor efficacy. These molecules, all of which contained either Leu or Phe at P1 and at least one Ser(Me) residue at P2 or P3, were also assessed in vitro for cellular cytotoxicity and potency against the active sites of both the constitutive and immunoproteasome. We found that while the bioavailibity ranged from 6 - 25% for these compounds, the dose dependent inhibition of proteasome activity in a given tissue was similar. Repeated (QDx2) PO administration was well tolerated at doses that resulted in significant (>80%) proteasome inhibition in most tissues, which is also seen with IV administration of carfilzomib. Interestingly, compounds with Phe at P1 were better tolerated than those with Leu at the same position when MTDs were compared to PD activity. When assessed for anti-tumor activity two compounds, PR-047 and PR-928, induced consistent responses across multiple tumor models. For both PR-047 and PR-928 the anti-tumor activity was equivalent to or better than IV administered carfilzomib. However, PR-047 was the only molecule that induced an anti-tumor response below the MTD, thus demonstrating an improved therapeutic window over carfilzomib and the other orally bioavailable analogs. The results from these studies have enabled a development program for PR-047 for the treatment of malignant diseases." @default.
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• W2263458534 date "2007-11-01" @default.
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• W2263458534 title "Pharmacodynamic, pharmacokinetic and anti-tumor properties of orally bioavailable inhibitors of the 20S proteasome" @default.
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