Substrates and inhibitors of prolyl oligopeptidase and methods of use thereof

Patent metadata

Field	Value
Publication number	US-10155789-B2
Application number	US-201715602709-A
Country	US
Kind code	B2
Filing date	May 23, 2017
Priority date	May 4, 2012
Publication date	Dec 18, 2018
Grant date	Dec 18, 2018

Abstract

Inhibitors of fibroblast activation protein alpha (FAP) and Prolyl Oligopeptidase (POP) are disclosed, along with their use in various therapies related to conditions, diseases, and disorders involving abnormal cell proliferation such as malignancies and angiogenesis, and in neural disorders such as Alzheimer's disease. Stalk portions of the inhibitor molecules, and substrates of FAP and POP, are also disclosed and may be used, for example, in screening methods for identifying such inhibitors.

First claim

What is claimed is:

1. A method of reducing or inhibiting activity of prolyl oligopeptidase (POP) in at least one cell or tissue which expresses POP, comprising:
administering to the POP-expressing cell or tissue a compound having the formula:
B-Xaa 1a -Sp-Xaa 2a -Cyc  (Formula II),

wherein:
B is a blocking group selected from the group consisting of aminobenzoyl (Abz), acetyl (Ac), benzoyl (Bz), benzyloxycarbonyl (Z), t-Butyloxycarbonyl (Boc), Furylacryloyl (Fa), Methoxysuccinyl (MeOSuc), Pyroglutamate (Pyr), Pyrazine, Phenylalanine, a peptide consisting of 1-3 natural amino acids, and Succinyl (Suc);
Xaa 1a is (a) a positively-charged amino acid, (b) a negatively-charged amino acid, or (c) a positively-charged or negatively-charged amino acid modified to comprise (1) a methylene group in substitution for the carbonyl group adjacent Sp, or (2) an isostere bond between Xaa 1a and Sp;
Sp is a spacer molecule having a length in a range of from 0.3 nm to 2.5 nm;
Xaa 2a is a positively-charged amino acid; and
Cyc is a boronyl proline, proline carbonitrile, nitrile pyrrolidone, or cyanopyrrolidine.

2. The method of claim 1 , wherein in the compound, Xaa 1a is selected from the group consisting of α,β-diaminopropionic acid; α,γ-diaminobutyric acid; ornithine; β-homoornithine; arginine; β-homoarginine; homoarginine; lysine; homolysine; β-homolysine; histidine; aspartic acid; and glutamic acid.

3. The method of claim 1 , wherein in the compound, Xaa 1a is selected from the group consisting of aspartic acid and glutamic acid.

4. The method of claim 1 , wherein in the compound, Xaa 2a is selected from the group consisting of α,β-diaminopropionic acid; α,γ-diaminobutyric acid; ornithine; β-homoornithine; arginine; β-homoarginine; homoarginine; lysine; homolysine; β-homolysine; and histidine.

5. The method of claim 1 , wherein in the compound, Sp is selected from the group consisting of γ-aminobutyric acid; ε-aminocaproic acid; 8-amino-3,6-dioxaoctanoic acid; 11-amino-3,6,9-trioxaundecanoic acid; 14-amino-3,6,9,12-tetraoxatetradecanoic acid; α-aminobutyric acid; 5-aminopentanoic acid; 6-aminohexanoic acid; 7-aminoheptanoic acid; 8-aminooctanoic acid; 3-(aminooxy)acetic acid; β-alanine; glycine; alanine; threonine; tryptophan; tyrosine; methionine; leucine; isoleucine; valine; serine; proline; ethylene glycol; PEG n (wherein n=1-6); propylene glycol; PPG n (wherein n=1-6); amino-PEG n -carboxy group (wherein n=1-6); amino-PPG n -carboxy (wherein n=1-6); and combinations thereof.

6. The method of claim 1 , wherein in the compound, Sp is leucine, isoleucine, valine, or alanine.

7. The method of claim 1 , wherein in the compound, Sp has a length in a range of from 0.6 nm to 1.75 nm.

8. The method of claim 1 , wherein in the compound, B is an acetyl, pyroglutamate, or succinyl; Xaa 1a is lysine; Sp is at least one of leucine, isoleucine, valine, or alanine; Xaa 2a is arginine; and Cyc is a boronyl proline or cyanopyrrolidine.

9. The method of claim 1 , wherein the compound further comprises a single amino acid or a peptide of 2 to 10 amino acids which extends from Cyc in the C-terminal direction.

10. The method of claim 1 , wherein the at least one POP-expressing cell or tissue is a cancer cell and/or an activated fibroblast cell.

11. A method of reducing or inhibiting activity of prolyl oligopeptidase (POP) in a subject suffering from a disorder for which the reduction or inhibition of POP provides a therapeutically-effective benefit, comprising:
administering to a subject in need of such therapy a compound having the formula:
B-Xaa 1a -Sp-Xaa 2a -Cyc  (Formula II),

wherein:
B is a blocking group selected from the group consisting of aminobenzoyl (Abz), acetyl (Ac), benzoyl (Bz), benzyloxycarbonyl (Z), t-Butyloxycarbonyl (Boc), Furylacryloyl (Fa), Methoxysuccinyl (MeOSuc), Pyroglutamate (Pyr), Pyrazine, Phenylalanine, a peptide consisting of 1-3 natural amino acids, and Succinyl (Suc);
Xaa 1a is (a) a positively-charged amino acid, (b) a negatively-charged amino acid, or (c) a positively-charged or negatively-charged amino acid modified to comprise (1) a methylene group in substitution for the carbonyl group adjacent Sp, or (2) an isostere bond between Xaa 1a and Sp;
Sp is a spacer molecule having a length in a range of from 0.3 nm to 2.5 nm;
Xaa 2a is a positively-charged amino acid; and
Cyc is a boronyl proline, proline carbonitrile, nitrile pyrrolidone, or cyanopyrrolidine.

12. The method of claim 11 , wherein the disorder for which the reduction or inhibition of POP provides a therapeutically-effective benefit is at least one of angiogenesis and cancer.

13. The method of claim 11 , wherein in the compound, Xaa 1a is selected from the group consisting of α,β-diaminopropionic acid; α,γ-diaminobutyric acid; ornithine; β-homoornithine; arginine; β-homoarginine; homoarginine; lysine; homolysine; β-homolysine; histidine; aspartic acid; and glutamic acid.

14. The method of claim 11 , wherein in the compound, Xaa 1a is selected from the group consisting of aspartic acid and glutamic acid.

15. The method of claim 11 , wherein in the compound, Xaa 2a is selected from the group consisting of α,β-diaminopropionic acid; α,γ-diaminobutyric acid; ornithine; β-homoornithine; arginine; β-homoarginine; homoarginine; lysine; homolysine; β-homolysine; and histidine.

16. The method of claim 11 , wherein in the compound, Sp is selected from the group consisting of γ-aminobutyric acid; ε-aminocaproic acid; 8-amino-3,6-dioxaoctanoic acid; 11-amino-3,6,9-trioxaundecanoic acid; 14-amino-3,6,9,12-tetraoxatetradecanoic acid; α-aminobutyric acid; 5-aminopentanoic acid; 6-aminohexanoic acid; 7-aminoheptanoic acid; 8-aminooctanoic acid; 3-(aminooxy)acetic acid; β-alanine; glycine; alanine; threonine; tryptophan; tyrosine; methionine; leucine; isoleucine; valine; serine; proline; ethylene glycol; PEG n (wherein n=1-6); propylene glycol; PPG n (wherein n=1-6); amino-PEG n -carboxy group (wherein n=1-6); amino-PPG n -carboxy (wherein n=1-6); and combinations thereof.

17. The method of claim 11 , wherein in the compound, Sp is leucine, isoleucine, valine, or alanine.

18. The method of claim 11 , wherein in the compound, Sp has a length in a range of from 0.6 nm to 1.75 nm.

19. The method of claim 11 , wherein in the compound, B is an acetyl, pyroglutamate, or succinyl; Xaa 1a is lysine; Sp is at least one of leucine, isoleucine, valine, or alanine; Xaa 2a is arginine; and Cyc is a boronyl proline or cyanopyrrolidine.

20. The method of claim 11 , wherein the compound further comprises a single amino acid or a peptide of 2 to 10 amino acids which extends from Cyc in the C-terminal direction.

Assignees

• Univ Oklahoma

Inventors

• Mckee Patrick A
• Jackson Kenneth W
• Christiansen Victoria J

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• C07K5/0821

  with the first amino acid being heterocyclic, e.g. His, Pro, Trp · CPC title

• C07K5/0819

  with the first amino acid being acidic · CPC title

• C07K5/0815

  with the first amino acid being basic · CPC title

• C07K5/06147

  and His-amino acid; Derivatives thereof · CPC title