Inhibitors of the 26s proteolytic complex and the 20s proteasome contained therein

• US 5,693,617 A
• Filed: 01/15/1995
• Issued: 12/02/1997
• Est. Priority Date: 03/15/1994
• Status: Expired due to Fees

• Current Assignee: ProScript, Inc. (Takeda Pharmaceutical Company Limited)
• Original Assignee: ProScript, Inc. (Takeda Pharmaceutical Company Limited)
• Inventors: Brand, Stephen, Stein, Ross L., Ma, Yu-Ting
• Primary Examiner(s): Johnson, Jerry D.
• Application Number:
  US08/404,866
• Time in Patent Office: 1,052 Days
• Field of Search: 560/20, 560/27, 560/31, 560/32, 560/41, 560/47, 560/159, 530/331, 514/18, 514/19
• US Class Current: 514/20.1
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 5/0202 containing the structure -NH-X-X-C(=0)-, X being an optionally substituted carbon atom or a heteroatom, e.g. beta-amino acids
• CPC Class Codes: C07K 5/06026 the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
• CPC Class Codes: C07K 5/06043 Leu-amino acid
• CPC Class Codes: C07K 5/06078 and aromatic or cycloaliphatic
• CPC Class Codes: C07K 5/06139 with the first amino acid being heterocyclic
• CPC Class Codes: C07K 5/06156 and Trp-amino acid; Derivatives thereof
• CPC Class Codes: C07K 5/06165 and Pro-amino acid; Derivatives thereof

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.

Claims

1. 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;

B¹ at each occurrence is independently selected from the group consisting of ##STR94## X is selected from the group consisting of ##STR95## X¹ at each occurrence and X² are independently selected from the group consisting of ##STR96## except that if B¹ is ##STR97## then X¹ must be ##STR98## R is hydrogen or together with the adjacent R¹, or R² if A=0, forms a nitrogen-containing heterocyclic ring;

R¹ at each occurrence, R², and R³ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and --CH₂ --R⁴,

where R⁴ is aryl, aralkyl, alkaryl, cycloalkyl or --Y--R⁵,

where Y is a chalcogen, and R⁵ is alkyl; and

A is 0, 1, or 2; and

wherein, stereochemically, B¹ --R¹ is D, L, or a mixture thereof and CH--R² and CH--R³ are independently L or a mixture of D and L.

2. The method of claim 1 wherein P is

3. The method of claim 2 wherein X¹ and X² are ##STR100##

4. The method of claim 3 wherein A is 1 or 2 and B¹ is ##STR101##

5. The method of claim 4 wherein R³ is isobutyl.

6. The method of claim 4 wherein R¹ at each occurrence and R² are independently selected from the group consisting of alkyl and --CH₂ --R⁴, where R⁴ is cyclohexyl or naphthyl.

7. The method of claim 6 wherein B¹ --R¹, CH--R², and CH--R³ are all of the L configuration.

8. The method of claim 1 wherein the proteasome inhibitor is selected from the group consisting of ##STR102##

9. The method of claim 1 wherein the proteasome inhibitor is selected from the group consisting of ##STR103##

10. A compound selected from the group consisting of ##STR104##

11. A compound selected from the group consisting of ##STR105##

12. 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##

13. 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##

14. 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;

B¹ at each occurrence is independently selected from the group consisting of ##STR109## X is selected from the group consisting of ##STR110## X¹ at each occurrence and X² are independently selected from the group consisting of ##STR111## except that if B¹ is ##STR112## then X¹ must be ##STR113## R is hydrogen or together with the adjacent R¹, or R² if A=0, forms a nitrogen-containing heterocyclic ring;

R¹ at each occurrence, R², and R³ are independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and --CH₂ --R⁴,

where R⁴ is aryl, aralkyl, alkaryl, cycloalkyl or --Y--R⁵,

where Y is a chalcogen, and R⁵ is alkyl; and

A is 0, 1, or 2; and

wherein, stereochemically, B¹ --R¹ is D, L, or a mixture thereof and CH--R² and CH--R² and CH--R³ are independently L or a mixture of D and L.

15. The method of claim 14 wherein P is

16. The method of claim 15 wherein X¹ and X² are ##STR115##

17. The method of claim 16 wherein A is 1 or 2 and B¹ is ##STR116##

18. The method of claim 17 wherein R³ is isobutyl.

19. The method of claim 17 wherein R¹ at each occurrence and R² are independently selected from the group consisting of alkyl and --CH₂ --R⁴, where R⁴ is cyclohexyl or naphthyl.

20. The method of claim 19 wherein B¹ --R¹, CH--R², and CH--R³ are all of the L-configuration.

21. The method of claim 14 wherein the proteasome inhibitor is selected from the group consisting of:

##STR117##

22. The method of claim 14 wherein the proteasome inhibitor is selected from the group consisting of ##STR118##