Transition-state Inhibitors of Pin1, alpha-Ketoamide-containing peptidomimetics, and synthesis thereof

• US 20070027067A1
• Filed: 05/12/2006
• Published: 02/01/2007
• Est. Priority Date: 05/13/2005
• Status: Abandoned Application

• Current Assignee: Virginia Tech Intellectual Properties, Inc.
• Original Assignee: Virginia Tech Intellectual Properties, Inc.
• Inventors: Etzkorn, Felicia
• Application Number:
  US11/383,085
• Publication Number:
  US 20070027067A1
• Time in Patent Office: Days
• US Class Current: 530/330
• 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: C07D 207/16 Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07F 9/572 Five-membered rings

Abstract

Novel α-ketoamide-containing peptidomimetics are provided, such as peptidomimetics containing an α-ketoamide Ser-Pro dipeptide analogue. The α-ketoamide is preferably incorporated into another molecule as a Pin1 inhibitor (such as a pentapeptide analogue Ac-Phe-Tyr-pSer-Pro-Arg-NH₂).

Claims

1. A peptidomimetic compound comprising an α

-ketoamide, wherein the peptidomimetic compound has anti-Pin1 activity.

2. The peptidomimetic compound of claim 1, wherein the α

-ketoamide is α

-ketoamide Ser-Pro dipeptide analogue.

3. The peptidomimetic compound of claim 2 wherein said compound is a pentapeptide.

4. A peptide compound having the general structural formula

R-α

-ketoamide-R′

where R and R′

can be the same or different, and each includes 1-20 amino acids.

5. The peptide compound of claim 4 wherein said α

-ketoamide moiety is based on a Ser-Pro dipeptide.

6. The peptide compound of claim 4 wherein said α

-ketoamide compound is modified with a phosphorus moiety.

7. An α

-ketoamide compound, wherein the α

-ketoamide compound is selected from the group consisting of;

wherein R includes a carbonyl group attached to the amine as an amide, and R′

includes an amine attached to the carbonyl as an amide.

8. The α

-ketoamide compound of claim 7 where each of R and R′

may be the same or different and each of R and R′

include one to twenty amino acids.

9. The α

-ketoamide compound of claim 7, wherein R is selected from the group consisting of the following 26 acid and acid chloride synthons where the connection to the α

-ketoamide molecule is made through the carboxylic acid moiety;

10. The α

-ketoamide compound of claim 7, wherein R′

is selected from the group consisting of the following 30 amine synthons where the connection to the α

-ketoamide molecule is made through the amine moiety;

11. A peptidomimetic compound containing an α

-ketoamide moiety selected from the group consisting of α

-ketoamide phosphoSer-Pro, phosphoThr-Pro or Glu-Pro and the corresponding α

-ketoamide phospho(D)Ser-Pro, phospho(D)Thr-Pro, and phospho(D)Glu-Pro dipeptide analogue.

12. A compound comprising an α

c-ketoamide and a peptide analogue, wherein the α

-ketoamides is one or both of;

(1) a transition state mimetic and (2) mimicks a transition-state “

twisted amide.”

13. The compound of claim 12, wherein the α

-ketoamide is α

-ketoamide Ser-Pro dipeptide analogue.

14. A method of synthesizing a peptidomimetic, comprising:

incorporating an α

-ketoamide into a molecule, wherein a peptidomimetic is constructed.

15. The method of claim 14, wherein the α

-ketoamide is an α

-ketoamide Ser-Pro dipeptide analogue.

16. The method of claim 14, wherein the molecule is a pentapeptide analogue Ac-Phe-Tyr-pSer-Pro-Arg-NH₂.