IP Library › Granted Patent US 10,278,957
Granted Patent B2
US 10,278,957 · App. 16/128,352 · Granted May 7, 2019

Opioid agonist peptides and uses thereof

Inventors: Sampath Kumar Anandan (Fremont, CA); Jie Zhang (Newark, CA); Ashok Bhandari (Pleasanton, CA); Gregory Thomas Bourne (Brisbane, AU); Brian Troy Frederick (Ben Lomond, CA); Larry C. Mattheakis (Cupertino, CA); David Liu (Newark, CA)
Assignee: Protagonist Therapeutics, Inc.
A61K31/4045A61K38/38A61P1/00A61P29/00
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 10,278,957
App. No.
16/128,352
Granted
May 7, 2019
Kind
B2
Abstract

The invention is directed to opioid agonist peptides and their use.

Claims (97)

1. An opioid agonist peptide comprising or consisting of an amino acid sequence of Formula Ia:

X1-X2-X3-X4-X5  (Formula Ia) (SEQ ID NO:357)

or a pharmaceutically acceptable salt or solvate thereof,

wherein:

X1 is Tyr, DMT, or Phe(4-COX);

X2 is any amino acid;

X3 is any amino acid;

X4 is Sar, or bhF unsubstituted or substituted with 2-Me, 3-Me, 4-Me, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-OH, 3-OH, or 4-OH; and

X5 is absent or any amino acid;

wherein DMT is 2,6-dimethyltyrosine;

Phe(4-COX) is substituted or unsubstituted

wherein X is substituted or unsubstituted OH or NH 2 ; and

provided that when X1 is Tyr; then X4 is bhF unsubstituted or substituted with 2-Me, 3-Me, 4-Me, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-OH, 3-OH, or 4-OH, and X5 is N-methylamino acid.

2. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide is according to Formula XIIIa, XIIIb, or XIIIc:

R 1 -DMT-X2-X3-bhF-X5-R 2   (XIIIa) (SEQ ID NO:343);

R 1 -Phe(4-COX)-X2-X3-bhF-X5-R 2   (XIIIb) (SEQ ID NO:344);

or

R 1 -Tyr-X2-X3-bhF-X5-R 2   (XIIIc) (SEQ ID NO:345);

wherein DMT, Phe(4-COX), X2, X3 and X5 are as described in claim 1 ; bhF is unsubstituted or substituted with 2-Me, 3-Me, 4-Me, 2-F, 3-F, 4-F, 2-Cl, 3-Cl, 4-Cl, 2-OH, 3-OH, or 4-OH; R 1 is H or acetyl; and R 2 is OH or NH 2 ;

provided that when the peptide is according to formula XIIIc, then X5 is a N-methylamino acid.

3. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein X3 is (D)Phe, Phe, Bip, His, Aba, Trp, homo-Phe, 1-Nal, Phe(4-F), Phe(4-CN), Tic, Phe(3,4-dichloro), Phe(4-tBu), Phe(3,4-dimethoxy), DPA, Gly, Sar, THP, Ala, Leu, Ile, Val, Aib, or Ala.

4. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the amino acid sequence is according to Formula XIVa, XIVb, or XIVc:

R 1 -DMT-X2-G-bhF-X5-R 2   (XIVa) (SEQ ID NO:346);

R 1 -Phe(DMC)-X2-G-bhF-X5-R 2   (XIVb) (SEQ ID NO:347);

or

R 1 -Tyr-X2-G-bhF-X5-R 2   (XIVc) (SEQ ID NO:348)

wherein Phe(DMC) is Phe(2,6-dimethyl-4-CONH 2 ); R 1 is H or acetyl; and R 2 is OH or NH 2 .

5. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein X2 is (D)Glu, (D)Arg, N(Me)-(D)Ala, (D)Ala, (D)Tic, (D)Lys, (D)Orn, (D)Thr, (D)Asp, or (D)Tyr.

6. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the amino acid sequence is according to Formula XVa, XVb, XVc, XVd, XVIa, XVIb, XVIc, or XVId:

R 1 -DMT-(D)Ala-G-bhF-X5-R 2   (XVa) (SEQ ID NO:349);

R 1 -DMT-(D)Asp-G-bhF-X5-R 2   (XVb) (SEQ ID NO:350);

R 1 -DMT-(D)Thr-G-bhF-X5-R 2   (XVc) (SEQ ID NO:351);

R 1 -DMT-(D)Glu-G-bhF-X5-R 2   (XVd) (SEQ ID NO:352);

R 1 -Phe(DMC)-(D)Ala-G-bhF-X5-R 2   (XVIa) (SEQ ID NO:353);

R 1 -Phe(DMC)-(D)Asp-G-bhF-X5-R 2   (XVIb) (SEQ ID NO:354);

R 1 -Phe(DMC)-(D)Thr-G-bhF-X5-R 2   (XVIc) (SEQ ID NO:355);

R 1 -Phe(DMC)-(D)Glu-G-bhF-X5-R 2   (XVId) (SEQ ID NO:356)

wherein R 1 is H or acetyl; and R 2 is OH or NH 2 .

7. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein X5 is (D)Glu, (D)Arg, N(Me)-(D)Ala, (D)Ala, (D)Tic, (D)Lys, (D)Orn, (D)Thr, (D)Asp, or (D)Tyr, Sar, N(Me)Phg, N(Me)Cha, N(Me)Tyr, N(Me)Nle, N(Me)Ile, N(Me)Ala, N(Me)Val, N(Me)Leu, N(Me)Phe.

8. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the amino acid sequence is according to Formula XVIIa, XVIIb, XVIIc, XVIId, XVIIe, XVIIf, XVIIg, XVIIh, XVIIi, XVIIj, XVIIk, XVIIl, XVIIIa, XVIIIb, XVIIIc, XVIIId, XVIIIe, XVIIIf, XVIIIg, XVIIIh, XVIIIi, XVIIIj, XVIIIk, or XVIIIl:

R 1 -DMT-(D)Ala-G-bhF-Sar-R 2   (XVIIa) (SEQ ID NO:43);

R 1 -DMT-(D)Asp-G-bhF-Sar-R 2   (XVIIb) (SEQ ID NO:82);

R 1 -DMT-(D)Thr-G-bhF-Sar-R 2   (XVIIc) (SEQ ID NO:82);

R 1 -DMT-(D)Glu-G-bhF-Sar-R 2   (XVIId) (SEQ ID NO:187);

R 1 -DMT-(D)Ala-G-bhF-NMeAla-R 2   (XVIIe) (SEQ ID NO:111);

R 1 -DMT-(D)Asp-G-bhF-NMeAla-R 2   (XVIIf) (SEQ ID NO:170);

R 1 -DMT-(D)Thr-G-bhF-NMeAla-R 2   (XVIIg) (SEQ ID NO:183);

R 1 -DMT-(D)Glu-G-bhF-NMeAla-R 2   (XVIIh) (SEQ ID NO:185);

R 1 -DMT-(D)Ala-G-bhF-NMeIle-R 2   (XVIIi) (SEQ ID NO:113);

R 1 -DMT-(D)Asp-G-bhF-NMeIle-R 2   (XVIIj) (SEQ ID NO:172);

R 1 -DMT-(D)Thr-G-bhF-NMeIle-R 2   (XVIIk) (SEQ ID NO:182);

R 1 -DMT-(D)Glu-G-bhF-NMeIle-R 2   (XVIIl) (SEQ ID NO:186);

R 1 -Phe(DMC)-(D)Ala-G-bhF-Sar-R 2   (XVIIIa) (SEQ ID NO:70);

R 1 -Phe(DMC)-(D)Asp-G-bhF-Sar-R 2   (XVIIIb) (SEQ ID NO:77);

R 1 -Phe(DMC)-(D)Thr-G-bhF-Sar-R 2   (XVIIIc) (SEQ ID NO:76);

R 1 -Phe(DMC)-(D)Glu-G-bhF-Sar-R 2   (XVIIId) (SEQ ID NO:330);

R 1 -Phe(DMC)-(D)Ala-G-bhF-NMeAla-R 2   (XVIIIe) (SEQ ID NO:217);

R 1 -Phe(DMC)-(D)Asp-G-bhF-NMeAla-R 2   (XVIIIf) (SEQ ID NO:331);

R 1 -Phe(DMC)-(D)Thr-G-bhF-NMeAla-R 2   (XVIIIg) (SEQ ID NO:332);

R 1 -Phe(DMC)-(D)Glu-G-bhF-NMeAla-R 2   (XVIIIh) (SEQ ID NO:333);

R 1 -Phe(DMC)-(D)Ala-G-bhF-NMeIle-R 2   (XVIIIi) (SEQ ID NO:218);

R 1 -Phe(DMC)-(D)Asp-G-bhF-NMeIle-R 2   (XVIIIj) (SEQ ID NO:334);

R 1 -Phe(DMC)-(D)Thr-G-bhF-NMeIle-R 2   (XVIIIk) (SEQ ID NO:335);

or

R 1 -Phe(DMC)-(D)Glu-G-bhF-NMeIle-R 2   (XVIIIl) (SEQ ID NO:336);

wherein R 1 is H or acetyl; and R 2 is OH or NH 2 .

9. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 2 , wherein R 1 is H.

10. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide is:

H-DMT-a-G-bhF-Sar-NH 2 (SEQ ID NO:43);

H-DMT-a-G-bhF-Sar-OH (SEQ ID NO:43);

H-DMT-a-G-bhF-N(Me)Ala-OH (SEQ ID NO:111);

H-DMT-(D)Thr-G-bhF-N(Me)Ala-OH (SEQ ID NO:183);

H-DMT-(D)Asp-G-bhF-Sar-OH (SEQ ID NO:83);

H-DMT-(D)Asp-G-bhF-Sar-NH 2 (SEQ ID NO:83);

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-Sar-OH (SEQ ID NO:70);

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-Sar-NH 2 (SEQ ID NO:70);

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF(4-F)-N(Me)Nle-OH (SEQ ID NO:166); or

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF(4-F)-N(Me)Nle-NH 2 (SEQ ID NO:166).

11. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide is:

H-DMT-a-G-bhF-Sar-NH 2 (SEQ ID NO:43); or

H-DMT-a-G-bhF-Sar-OH (SEQ ID NO:43).

12. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide is:

H-DMT-a-G-bhF-N(Me)Ala-OH (SEQ ID NO:111); or

H-DMT-(D)Thr-G-bhF-N(Me)Ala-OH (SEQ ID NO:183).

13. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide is:

H-DMT-(D)Asp-G-bhF-Sar-OH (SEQ ID NO:83); or

H-DMT-(D)Asp-G-bhF-Sar-NH 2 (SEQ ID NO:83).

14. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide is:

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-Sar-OH (SEQ ID NO:70); or

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-Sar-NH 2 (SEQ ID NO:70).

15. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide is:

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF(4-F)-N(Me)Nle-OH (SEQ ID NO:166); or

H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF(4-F)-N(Me)Nle-NH 2 (SEQ ID NO:166).

16. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide is H-DMT-a-G-bhF-Sar-NH 2 (SEQ ID NO:43).

17. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide is H-DMT-(D)Thr-G-bhF-N(Me)Ala-OH (SEQ ID NO:183).

18. The opioid agonist peptide or pharmaceutically acceptable salt or solvate thereof of claim 1 , wherein the peptide is H-Phe(2,6-dimethyl-4-CONH 2 )-a-G-bhF-Sar-NH 2 (SEQ ID NO:70).

19. A pharmaceutical composition comprising the opioid agonist peptide or pharmaceutically acceptable salt thereof of claim 1 , and a pharmaceutically acceptable diluent, carrier, or excipient.

Assignments (3)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 19, 2020
From: ANANDAN, SAMPATH KUMAR; ZHANG, JIE; BHANDARI, ASHOK; BOURNE, GREGORY THOMAS; FREDERICK, BRIAN TROY; MATTHEAKIS, LARRY C.; LIU, DAVID; MEHROTRA, MUKUND M.
To: PROTAGONIST THERAPEUTICS, INC.
Reel/Frame 052167/0717 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 28, 2019
From: MEHROTRA, MUKUND M.
To: PROTAGONIST THERAPEUTICS, INC.
Reel/Frame 049622/0339 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 3, 2018
From: ANANDAN, SAMPATH KUMAR; ZHANG, JIE; BHANDARI, ASHOK; BOURNE, GREGORY THOMAS; FREDERICK, BRIAN TROY; MATTHEAKIS, LARRY C.; LIU, DAVID
To: PROTAGONIST THERAPEUTICS, INC.
Reel/Frame 047052/0246 →
Continuity (3)
Provisional Application 62556900 · Sep 11, 2017
Provisional Application 62663660 · Apr 27, 2018
Related Publication 20190076400A1 · Mar 14, 2019
Cited By (4)
US 12,478,617 US 12,552,836 US 12,655,185 US 12,673,974