Cyclic peptides as ADAM protease inhibitors

Patent metadata

Field	Value
Publication number	US-9546198-B2
Application number	US-201514798825-A
Country	US
Kind code	B2
Filing date	Jul 14, 2015
Priority date	Oct 12, 2007
Publication date	Jan 17, 2017
Grant date	Jan 17, 2017

Abstract

The invention relates to a method for inhibiting an ADAM protease, comprising inhibiting binding to an integrin-binding loop of a disintegrin domain in the ADAM protease. Also provided are cyclic peptides which inhibit binding to an integrin-binding loop of an ADAM protease, as well as associated pharmaceutical compositions, uses and methods of treatment.

First claim

The invention claimed is:

1. A cyclic peptide of formula I:

wherein X 0 , X 1 , X 2 , and X 3 each independently represents an amino acid residue;
wherein each amino acid residue in the cyclic peptide is joined by a peptide bond;
wherein each X 0 may be the same or different;
wherein X 1 , X 2 , and X 3 are selected such that the cyclic peptide comprises one of the following amino acid sequences: KDM, ARQ, DSD, NAT, VRQ, and TDD; and
wherein n is 0 to 4;
or a pharmaceutically acceptable salt thereof.

2. The cyclic peptide according to claim 1 , wherein the cyclic peptide has the formula II:

wherein α 0 , α 1 , α 2 and α 3 each independently represents an alpha-amino acid residue;
wherein each α 0 may be the same or different;
wherein D represents a D -amino acid residue;
wherein each amino acid residue in the cyclic peptide is joined by a peptide bond;
wherein m is 1 to 3; and
wherein α 1 , α 2 and α 3 are selected such that the cyclic peptide comprises one of the following amino acid sequences: KDM, TSE, ARQ, DSD, NAT, VRQ, and TDD;
or a pharmaceutically acceptable salt thereof.

3. The cyclic peptide according to claim 2 , wherein the cyclic peptide has the formula III:

wherein R α0 , R α1 , R α2 and R α3 each independently represents an alpha-amino acid side-chain;
wherein each R α0 may be the same or different;
wherein R D represents a D amino acid side-chain;
wherein p is 1 to 3; and
wherein R α1 , R α2 and R α3 are selected such that the cyclic peptide comprises one of the following amino acid sequence: KDM, TSE, ARQ, DSD, NAT, VRQ, and TDD;
or a pharmaceutically acceptable salt thereof.

4. The cyclic peptide according to claim 1 , wherein the cyclic peptide comprises a sequence KDM.

5. The cyclic peptide according to claim 1 , wherein n, X 0 , X 1 , X 2 , and X 3 are selected such that the cyclic peptide comprises one of the following amino acid sequences: RPKKDM (SEQ ID NO: 2), REQARQ (SEQ ID NO: 8), RDDSD (SEQ ID NO: 10), QEAINAT (SEQ ID NO: 11), REQVRQ (SEQ ID NO: 14), and RPPTDD (SEQ ID NO: 16).

6. The cyclic peptide according to claim 5 , wherein the cyclic peptide comprises a sequence RPKKDM (SEQ ID NO: 2).

7. The cyclic peptide according to claim 1 , which is cyclo(RGkTSE), cyclo(RPkKDM), cyclo(REqARQ), cyclo(RdDSD), cyclo(QEAiNAT), cyclo(REqVRQ), or cyclo(RPpTDD), wherein a lower case letter represents a D amino acid and an upper case letter represents an alpha amino acid, or a pharmaceutically acceptable salt thereof.

8. The cyclic peptide according to claim 7 , which is cyclo(Arg-Pro-{ D -Lys}-Lys-Asp-Met) or a pharmaceutically acceptable salt thereof.

9. A composition comprising the cyclic peptide as set out in claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

10. A cyclic peptide of formula I:

wherein X 0 , X 1 , X 2 and X 3 each independently represents an amino acid residue;
wherein each amino acid residue in the cyclic peptide is joined by a peptide bond;
wherein each X 0 may be the same or different;
wherein X 0 , X 1 , X 2 and X 3 are selected such that the cyclic peptide comprises an amino acid sequence RPTRGD (SEQ ID NO: 6);
and wherein n is 3 or 4;
or a pharmaceutically acceptable salt thereof.

11. A cyclic peptide which is cyclo(RPtRGD), wherein a lower case letter represents a D amino acid and an upper case letter represents an alpha amino acid, or a pharmaceutically acceptable salt thereof.

12. A cyclic peptide of formula II:

wherein α 0 , α 1 , α 2 and α 3 each independently represents an alpha-amino acid residue;
wherein each α 0 may be the same or different;
wherein D represents a D-amino acid residue;
wherein each amino acid residue in the cyclic peptide is joined by a peptide bond;
wherein m is 1 to 3; and
wherein α 1 , α 2 and α 3 are selected such that the cyclic peptide comprises one of the following amino acid sequences: KDM, TSE, KDE, SNS, ARQ, MGD, DSD, NAT, VRQ, ATD and TDD;
or a pharmaceutically acceptable salt thereof.

13. The cyclic peptide according to claim 12 , wherein the cyclic peptide has the formula III:

wherein R α0 , R α1 , R α2 , and R α3 , each independently represents an alpha-amino acid side-chain;
wherein each R α0 may be the same or different;
wherein R D represents a D-amino acid side-chain;
wherein p is 1 to 3; and
wherein R +1 , R α2 , and R α3 are selected such that the cyclic peptide comprises one of the following amino acid sequences: KDM, TSE, KDE, SNS, ARQ, MGD, DSD, NAT, VRQ, ATD and TDD;
or a pharmaceutically acceptable salt thereof.

14. A cyclic peptide of formula I:

wherein X 0 , X 1 , X 2 , and X 3 each independently represents an amino acid residue;
wherein each amino acid residue in the cyclic peptide is joined by a peptide bond;
wherein each X 0 may be the same or different;
X 1 , X 2 , and X 3 are selected such that the cyclic peptide comprises one of the following amino acid sequences: RPKKDM (SEQ ID NO:2), RPAKDE (SEQ ID NO: 5), REQARQ (SEQ ID NO: 8), RQAMGD (SEQ ID NO: 9), RDDSD (SEQ ID NO: 10), QEAINAT (SEQ ID NO: 11), RAAKDE (SEQ ID NO: 12), RGSSNS (SEQ ID NO: 13), REQVRQ (SEQ ID NO: 14), RPAATD (SEQ ID NO: 15), and RPPTDD (SEQ ID NO: 16); and
wherein n is 3 or 4;
or a pharmaceutically acceptable salt thereof.

15. A cyclic peptide which is cyclo(RGkTSE), cyclo(RPaKDE), cyclo(RPkKDM), cyclo(RDsSNS), cyclo(REqARQ), cyclo(RQaMGD), cyclo(RdDSD), cyclo(QEAiNAT), cyclo(RAaKDE), cyclo(RGsSNS), cyclo(REqVRQ), cyclo(RPaATD), or cyclo(RPpTDD), wherein a lower case letter represents a D-amino acid residue and an upper case letter represents an alpha amino acid residue, or a pharmaceutically acceptable salt thereof.

16. The cyclic peptide according to claim 15 which is cyclo(Arg-Pro-{D-Lys}-Lys-Asp-Met), or a pharmaceutically acceptable salt thereof.

Assignees

• King S College London
• Cancer Res Tech Ltd

Inventors

• Bartsch Joerg
• Koller Garrit

Classifications

• A61P37/08

  Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14) · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• C12Y304/24046

  Adamalysin (3.4.24.46) · CPC title

• C07K5/12

  Cyclic peptides {with only normal peptide bonds in the ring} · CPC title