Oligomer-Protease Inhibitor Conjugates
Provided are small molecule drugs that are chemically modified by covalent attachment of a water soluble oligomer. A conjugate of the invention, when administered by any of a number of administration routes, exhibits characteristics that are different from the small molecule drug not attached to the water soluble oligomer.
1 . A compound comprising a residue of a protease inhibitor covalently attached, either directly or through one or more atoms via a stable linkage, to a water-soluble, non-peptidic oligomer.
2 . The compound of claim 1 , with the proviso that the protease inhibitor is not a HIV protease inhibitor.
3 . The compound of claim 1 , wherein the protease inhibitor is a hepatitis protease inhibitor.
4 . The compound of claim 3 , wherein the hepatitis protease inhibitor is an NS3 protease inhibitor.
5 . The compound of claim 3 , wherein the hepatitis protease inhibitor is an HCV protease inhibitor.
6 . The compound of claim 3 , wherein the hepatitis protease inhibitor is an HBV protease inhibitor.
7 . The compound of claim 1 , having the following structure:
wherein:
Protease Inhibitor is a residue of a small molecule hepatitis protease inhibitor;
(a) is an integer having a value of 1-3,
X, in each occurrence, is a stable linkage; and
POLY, in each occurrence, is a water-soluble, non-peptidic oligomer.
8 . The compound of claim 1 , wherein the water-soluble, non-peptidic oligomer possesses from 1-30 monomers.
9 . The compound of claim 8 , wherein the water-soluble non-peptidic oligomer possesses a number of monomer subunits selected from 1, 2, 3, 4, 5, 6, 7, 9 and 10.
10 . The compound of claim 1 , where the water-soluble non-peptidic oligomer is an oligomeric (ethylene oxide).
11 . The compound of claim 10 , wherein the oligomeric (ethylene oxide) possesses an alkoxy or hydroxyl end-capping moiety.
12 . The compound of claim 1 , wherein the protease inhibitor is selected from Telaprevir, Boceprevir, ITMN-191 and BILN-2061.
13 . The compound of claim 12 , wherein the stable linkage is selected from ether, carbamate, amide, sulfonylamide, and urea.
14 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable excipient.
15 . A dosage form comprising the compound of claim 1 .
16 . Use of a compound of claim 1 for treating a condition responsive to treatment with the protease inhibitor.