IP Library › Granted Patent US 10,626,146

Granted Patent B2

US 10,626,146 · App. 16/039,813 · Granted Apr 21, 2020

α4β7 thioether peptide dimer antagonists

Inventors: Ashok Bhandari (Pleasanton, CA); Dinesh V. Patel (Fremont, CA); Genet Zemede (San Jose, CA); Brian Troy Frederick (Ben Lomond, CA); Larry C. Mattheakis (Cupertino, CA); David Liu (Newark, CA)

Assignee: Protagonist Therapeutics, Inc.

C07K7/56 A61K38/12 A61K47/54 A61K47/545 A61K47/60 A61K47/64 C07K7/06 C07K7/08 C07K14/70546 A61K38/00

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Quick Facts

Patent No.: US 10,626,146
App. No.: 16/039,813
Granted: Apr 21, 2020
Kind: B2

External Links

USPTO Patent Center↗ Full Patent PDF↗

Abstract

The invention relates to thioether monomer and dimer peptide molecules which inhibit binding of α4β7 to the mucosal addressing cell adhesion molecule (MAdCAM) in vivo.

Claims (944)

1. A peptide molecule comprising a structure of Formula (VI):

(Formula VI)

Xaa 1 -Xaa 2 -Xaa 3 -Xaa 4 -Xaa 5 -Xaa 6 -Xaa 7 -Xaa 8 -Xaa 9 -

Xaa 10 -Xaa 11

or a pharmaceutically acceptable salt thereof, wherein

Xaa 1 is a 2-Me-benzoyl group capable of forming a thioether bond with Xaa 7 ;

Xaa 2 is N(alpha)-Me-Arg;

Xaa 3 is Ser;

Xaa 4 is Asp;

Xaa 5 is Thr;

Xaa 6 is Leu;

Xaa 7 is selected from the group consisting of Cys, Pen, and D-Pen;

Xaa 8 is selected from the group consisting of aromatic ring substituted Phe, Bpa, Phe(3-Me), Phe(2-Me), Phe(2-CF 3 ), β-Me-Phe, 4-Me-Phe, and corresponding D-amino acids;

Xaa 9 is Glu D-Glu, or β-HGlu;

Xaa 10 is selected from the group consisting of Lys, N-Me-Lys, and corresponding D-amino acids; and

Xaa 11 is absent, wherein the peptide further comprises a thioether bond between Xaa 1 and Xaa 7 ;

wherein Bpa is

and

wherein the peptide molecule or pharmaceutically acceptable salt thereof inhibits binding of α4β7 to MAdCAM.

2. The peptide molecule or pharmaceutically acceptable salt thereof of claim 1 , further comprising a terminal modifying group selected from the group consisting of DIG, PEG4, PEG13, PEG25, PEG1K, PEG2K, PEG4K, PEG5K, Polyethylene glycol having molecular weight from 400 Da to 40,000 Da, IDA, Ac-IDA, ADA, Glutaric acid, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, AADA, suitable aliphatic acids, suitable aromatic acids, and heteroaromatic acids.

3. The peptide molecule or pharmaceutically acceptable salt thereof of claim 1 , wherein the C-terminus of the peptide molecule further comprises a modifying group.

4. The peptide molecule or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide molecule is a monomer.

5. The peptide molecule or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide molecule is a dimer.

6. The peptide molecule or pharmaceutically acceptable salt thereof of claim 5 , comprising two peptide molecules dimerized by a linker.

7. The peptide molecule or pharmaceutically acceptable salt thereof of claim 6 , where in the linker is selected from the group consisting of: DIG, PEG4, PEG4-biotin, PEG13, PEG25, PEG1K, PEG2K, PEG3.4K, PEG4K, PEG5K, IDA, ADA, Boc-IDA, Glutaric acid, Isophthalic acid, 1,3-phenylenediacetic acid, 1,4-phenylenediacetic acid, 1,2-phenylenediacetic acid, Triazine, Boc-Triazine, IDA-biotin, PEG4-Biotin, AADA, suitable aliphatics, aromatics, heteroaromatics, and polyethylene glycol based linkers having a molecular weight from approximately 400 Da to approximately 40,000 Da.

8. The peptide molecule or pharmaceutically acceptable salt thereof of claim 6 , wherein the two peptide molecules are dimerized via their C-termini.

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

10. The pharmaceutical composition of claim 9 , wherein the pharmaceutical composition is formulated for oral delivery.

11. The pharmaceutical composition of claim 9 , further comprising an enteric coating.

12. The pharmaceutical composition of claim 11 , wherein the enteric coating releases the pharmaceutical composition within a subject's lower gastrointestinal system.

13. The peptide molecule or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide molecule is any one of the peptides depicted in any row of the following table:

SEQ

Bond

(thioether)

2-Benzyl

N—Me—R

Pen

F(CF3)

NH 2

242

(thioether)

2-Benzyl

N—Me—R

Pen

F(2-

NH 2

carbamoyl)

243

(thioether)

2-Benzyl

N—Me—R

Pen

F(3-

NH 2

carbamoyl)

244

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-COOH)

NH 2

245

(thioether)

2-Benzyl

N—Me—R

Pen

F(2,4-Cl)

NH 2

246

(thioether)

2-Benzyl

N—Me—R

Pen

F(3,4-Cl)

NH 2

247

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-OMe)

NH 2

250

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

NH 2

251

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-F)

NH 2

266

(thioether)

2-Benzyl

N—Me—R

Pen

F(4CF3)

NH 2

269

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

NH 2

270

(thioether)

2-Benzyl

N-Me-R

Pen

F(4tBu)

NH 2

HomoGlu

271

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-COOH)

NH 2

272

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-COOH)

NH 2

273

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-COOH)

NH 2

274

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-COOH)

NH 2

HomoGlu

275

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-COOH)

NH 2

HomoGlu

276

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-COOH)

NH 2

HomoGlu

285

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

N—Me—K

NH 2

286

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

N—Me—k

NH 2

287

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

b-Homo

N—Me—K

NH 2

Glu

288

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

b-Homo

N—Me—k

NH 2

Glu

wherein “2-benzyl” indicates 2-methylbenzoyl, lower case letters indicate D-amino acids; the amino acid residues are numbers Xaa 1-10 , in accordance with Formula (VI); and “(thioether)” indicates each peptide molecule is cyclized via an intramolecular thioether bond between the amino acid residue or moiety shown at position 1 and the amino acid residue shown at position 7.

14. The peptide molecule or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide molecule is any one of the peptide dimers depicted in any row of the following table:

SEQ

Lin-

Bond

ker

166

(thioether)

2-Benzyl

N—Me—R

Pen

F(CF3)

NH 2 ) 2

DIG

176

(thioether)

2-Benzyl

N—Me—R

Pen

F(2,4-

NH 2 ) 2

DIG

diCl)

177

(thioether)

2-Benzyl

N—Me—R

Pen

F(3,4-

NH 2 ) 2

DIG

diCl)

222

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-tBu)

bHE

NH 2 ) 2

DIG

223

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-tBu)

bHE

OH) 2

DIG

347

(thioether)

2-Benzyl

N—Me—R

Pen

F(2,4-Cl)

NH 2 ) 2

DIG

348

(thioether)

2-Benzyl

N—Me—R

Pen

F(2-

NH 2 ) 2

DIG

carbamoyl)

349

(thioether)

2-Benzyl

N—Me—R

Pen

F(3,4-Cl)

NH 2 ) 2

DIG

350

(thioether)

2-Benzyl

N—Me—R

Pen

F(3-

NH 2 ) 2

DIG

carbamoyl)

351

(thioether)

2-Benzyl

N—Me—R

Pen

F(4CF3)

NH 2 ) 2

DIG

352

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-

NH 2 ) 2

DIG

COOH)

353

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-

NH 2 ) 2

DIG

COOH)

356

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-

NH 2 ) 2

DIG

COOH)

HomoGlu

359

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-F)

NH 2 ) 2

DIG

360

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-OMe)

NH 2 ) 2

DIG

361

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

NH 2 ) 2

DIG

362

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

NH 2 ) 2

DIG

363

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

NH 2 ) 2

DIG

HomoGlu

364

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

N—Me—K

NH 2 ) 2

DIG

365

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

N—Me—k

NH 2 ) 2

DIG

366

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

N—Me—K

NH 2 ) 2

DIG

HomoGlu

367

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

N—Me—k

NH 2 ) 2

DIG

HomoGlu

wherein “2-benzyl” indicates 2-methylbenzoyl, lower case letters indicate D-amino acids; the amino acid residues are numbers Xaa 1-10 , in accordance with Formula (VI); “(thioether)” indicates each monomer subunit of the peptide dimer is cyclized via an intramolecular thioether bond between the amino acid residue or moiety shown at position 1 and the amino acid residue shown at position 7; and the peptide monomer subunits of the peptide dimers are dimerized at their C-termini by the indicated DIG, ADA, IDA, IDA-Palm, IDA-Lauryl, IDA-oleoyl, or IDA-PEG linker.

15. The peptide molecule or pharmaceutically acceptable salt thereof of claim 13 , wherein the peptide molecule is any one of the peptides depicted in any row of the following table:

SEQ

Bond

(thioether)

2-Benzyl

N—Me—R

Pen

F(CF3)

NH 2

244

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-COOH)

NH 2

270

(thioether)

2-Benzyl

N—Me—R

Pen

F(4tBu)

NH 2

HomoGlu

274

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-COOH)

NH 2

HomoGlu

16. The peptide molecule or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide molecule is any one of the peptide dimer depicted in any row of the following table:

SEQ

Bond

Linker

161

(thioether)

2-Benzyl

N—Me—R

Pen

2-NaI

b-H-E

NH 2 ) 2

DIG

164

(thioether)

2-Benzyl

N—Me—R

Pen

b-H-E

NH 2 ) 2

DIG

165

(thioether)

2-Benzyl

N—Me—R

Pen

b-H-E

NH 2 ) 2

DIG

167

(thioether)

2-Benzyl

N—Me—R

Pen

1NaI

NH 2 ) 2

DIG

352

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-

NH 2 ) 2

DIG

COOH)

356

(thioether)

2-Benzyl

N—Me—R

Pen

F(4-

NH 2 ) 2

DIG

COOH)

HomoGlu

17. The peptide molecule or pharmaceutically acceptable salt thereof of claim 1 , wherein the peptide molecule is a peptide dimer and each peptide monomer subunit is any one of the peptides depicted in any row of the following table:

SEQ

Bond

(thioether)

2-Benzyl

N—Me—R

Pen

2-NaI

b-H-E

NH 2

(thioether)

2-Benzyl

N—Me—R

Pen

b-H-E

NH 2

(thioether)

2-Benzyl

N—Me—R

Pen

b-H-E

NH 2

(thioether)

2-Benzyl

N—Me—R

Pen

F(CF3)

NH 2

296

(thioether)

2-Benzyl

N—Me—R

Pen

2-NaI

N—Me—k

NH 2

HomoGlu

wherein “2-benzyl” indicates 2-methylbenzoyl, lower case letters indicate D-amino acids; the amino acid residues are numbers Xaa 1-10 , in accordance with Formula (VI); “(thioether)” indicates each monomer subunit of the peptide dimer is cyclized via an intramolecular thioether bond between the amino acid residue or moiety shown at position 1 and the amino acid residue shown at position 7; and the peptide monomer subunits of the peptide dimers are dimerized at their C-termini by DIG, ADA, IDA, IDA-Palm, IDA-Lauryl, IDA-oleoyl, or IDA-PEG linker.

18. The peptide dimer or pharmaceutically acceptable salt thereof of claim 14 , wherein each peptide comprises the sequence:

2-methylbenzoyl-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homo-Glu)-(D-Lys)(SEQ ID NO:270),

wherein the two peptides are linked by a linker moiety; the linker moiety is bound to the D-Lys amino acids of the two peptides; the linker moiety is diglycolic acid (DIG); and each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen.

19. The peptide dimer or pharmaceutically acceptable salt thereof of claim 14 , wherein each peptide comprises the sequence:

2-methylbenzoyl-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homo-Glu)-(D-Lys)-OH (SEQ ID NO:223),

wherein each of the two peptides comprises a thioether bond between the 2-methylbenzoyl and the Pen, wherein the two peptides are linked by a linker moiety bound to the D-Lys amino acids of the two peptides, and wherein the linker moiety is diglycolic acid (DIG).

20. The peptide dimer or pharmaceutically acceptable salt thereof of claim 14 , wherein each peptide comprises the sequence:

2-methylbenzoyl-(N-Me-Arg)-Ser-Asp-Thr-Leu-Pen-Phe(4-tBu)-(β-homo-Glu)-(D-Lys)-NH 2 (SEQ ID NO:222),

21. The peptide dimer compound or pharmaceutically acceptable salt thereof of claim 18 , wherein the peptide dimer compound or pharmaceutically acceptable salt thereof is an acetate salt of the peptide dimer compound.

22. A pharmaceutical composition comprising the peptide dimer compound or pharmaceutically acceptable salt thereof of claim 18 , and a pharmaceutically acceptable excipient, carrier or diluent.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 7, 2020

From: LIU, DAVID Y.

To: PROTAGONIST THERAPEUTICS, INC.

Reel/Frame 051439/0603 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Oct 8, 2018

From: BHANDARI, ASHOK; PATEL, DINESH V.; ZEMEDE, GENET; FREDERICK, BRIAN TROY; MATTHEAKIS, LARRY C.

To: PROTAGONIST THERAPEUTICS, INC.

Reel/Frame 047206/0032 →

Continuity (7)

Continuation 15614047 · Jun 5, 2017

Continuation 14714198 · May 15, 2015

Provisional Application 62058499 · Oct 1, 2014

Provisional Application 62058501 · Oct 1, 2014

Provisional Application 61994717 · May 16, 2014

Provisional Application 61994699 · May 16, 2014

Related Publication 20190016756A1 · Jan 17, 2019

Cited By (4)

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