Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein
AssigneeProScript, Inc.
InventorsRoss L. Stein, Yu-Ting Ma, Stephen Brand
Life of this patent
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Abstract
Disclosed herein is a method for reducing the rate of degradation of proteins in an animal comprising contacting cells of the animal with certain proteasome inhibitors. The structure of the inhibitors are also disclosed.
Claims22
A method for reducing the rate of loss of muscle mass in an animal comprising contacting cells of the muscle with a proteasome inhibitor of the structure:
- ##STR93## where P is an amino-group-protecting moiety;
- B.sup.1 at each occurrence is independently selected from the group consisting of ##STR94## X is selected from the group consisting of ##STR95## X.sup.1 at each occurrence and X.sup.2 are independently selected from the group consisting of ##STR96## except that if B.sup.1 is ##STR97## then X.sup.1 must be ##STR98## R is hydrogen or together with the adjacent R.sup.1, or R.sup.2 if A=0, forms a nitrogen-containing heterocyclic ring;
- R.sup.1 at each occurrence, R.sup.2, and R.sup.3 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and --CH.sub.2 --R.sup.4,
- where R.sup.4 is aryl, aralkyl, alkaryl, cycloalkyl or --Y--R.sup.5,
- where Y is a chalcogen, and R.sup.5 is alkyl;
- and
- A is 0, 1, or 2;
- and wherein, stereochemically, B.sup.1 --R.sup.1 is D, L, or a mixture thereof and CH--R.sup.2 and CH--R.sup.3 are independently L or a mixture of D and L.
A compound selected from the group consisting of ##STR104##
A compound selected from the group consisting of ##STR105##
A method for reducing the rate of intracellular protein breakdown in an animal comprising contacting cells of the animal with a proteasome inhibitor selected from the group consisting of:
- ##STR106##
A method for reducing the rate of intracellular protein breakdown in an animal comprising contacting cells of the animal with a proteasome inhibitor selected from the group consisting of ##STR107##
A method for reducing the rate of degradation of p53 protein in an animal comprising administering to said animal a proteasome inhibitor of the structure:
- ##STR108## where P is an amino-group-protecting moiety;
- B.sup.1 at each occurrence is independently selected from the group consisting of ##STR109## X is selected from the group consisting of ##STR110## X.sup.1 at each occurrence and X.sup.2 are independently selected from the group consisting of ##STR111## except that if B.sup.1 is ##STR112## then X.sup.1 must be ##STR113## R is hydrogen or together with the adjacent R.sup.1, or R.sup.2 if A=0, forms a nitrogen-containing heterocyclic ring;
- R.sup.1 at each occurrence, R.sup.2, and R.sup.3 are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and --CH.sub.2 --R.sup.4,
- where R.sup.4 is aryl, aralkyl, alkaryl, cycloalkyl or --Y--R.sup.5,
- where Y is a chalcogen, and R.sup.5 is alkyl;
- and
- A is 0, 1, or 2;
- and wherein, stereochemically, B.sup.1 --R.sup.1 is D, L, or a mixture thereof and CH--R.sup.2 and CH--R.sup.2 and CH--R.sup.3 are independently L or a mixture of D and L.
Dependencies are inferred from the claim text.