# US 7,407,934 B2 · Methods for regulating postprandial blood glucose

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- Number: US 7,407,934 B2
- Document ID: US7407934B2
- Status: Granted
- Kind: B2
- Application number: 10/643,681
- Filed: 2003-08-18
- Published: 2004-05-20
- Granted: 2008-08-05
- Earliest claimed: 1993-09-07
- Assignees: Amylin Pharmaceuticals, Inc.
- Inventors: Orville G. Kolterman; Andrew A. Young; Timothy J. Rink; Kathleen Ann Keating Brown
- Web page: https://patentgrep.com/patent/US7407934B2

## CPC

- A61K 38/23: Calcitonins
- A61K 38/22: Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin A61K38/33, e.g. corticotropin A61K38/35)
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/06: Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 25/02: for peripheral neuropathies
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

Methods for treating conditions associated with elevated, inappropriate or undesired post-prandial blood glucose levels are disclosed which comprise administration of an effective amount of an amylin agonist alone or in conjunction with other anti-gastric emptying agents. Methods for reducing gastric motility and delaying gastric emptying for therapeutic and diagnostic purposes are also described.

## Claims

### Claim 1

A method of reducing or moderating a postprandial rise in plasma glucose in a mammal comprising administering to said mammal in need of reducing or moderating a postprandial rise in plasma glucose an amylin agonist analogue in an amount effective to reduce or moderate a postprandial rise in plasma glucose, wherein the amylin agonist analogue is a peptide having the amino acid sequence selected from the group consisting of
a) 1A1-X-Asn-Thr-5-Ala-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E1- 20F1-G1-Asn-H1-Gly-25Pro-I1-Leu-J1-Pro-30Thr-K1-Val-Gly-Ser-35Asn-Thr-Tyr-Z (SEQ ID NO:42)
wherein
A1 is Lys, Ala, Ser or hydrogen;
B1 is Ala, Ser or Thr;
C1 is Val, Leu or Ile;
D1 is His or Arg;
E1 is Ser or Thr;
F1 is Ser, Thr, Gln or Asn;
G1 is Asn, Gln or His;
H1 is Phe, Leu or Tyr;
I1 is Ile, Val, Ala or Leu;
J1 is Ser, Pro, Leu, Ile or Thr;
K1 is Asn, Asp or Gln;
X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage,
wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy, and
provided that when
(i) A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Val, J1 is Pro and K1 is Asn; or
(ii) A1 is Lys, B1 is Ala, C1 is Val, D1 is His, E1 is Ser, F1 is Asn, G1 is Asn, H1 is Leu, I1 is Val, J1 is Ser and K1 is Asn;
then one or more of A1 to K1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloaklyamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy;
b) 1A1—X—Asn—Thr—5Ala—Thr—Y—Ala—Thr—10Gln—Arg—Leu—B1—Asn—15Phe—Leu—C1—D1—E1—20F1—G1—Asn—H1—Gly—25I1—J1—Leu—Pro—Pro—30Thr—K1—Val—Gly'Ser-35Asn—Thr—Tyr—Z (SEQ ID NO:44)
wherein
A1 is Lys, Ala, Ser or hydrogen;
B1 is Ala, Ser or Thr;
C1 is Val, Leu or Ile;
D1 is His or Arg;
E1 is Ser or Thr;
F1 is Ser, Thr, Gln or Asn;
G1 is Asn, Gln or His;
H1 is Phe, Leu or Tyr;
I1 is Ala or Pro;
J1 is Ile, Val, Ala or Leu;
K1 is Asn, Asp or Gln;
X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage,
wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and
provided that when
A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Pro, J1 is Val and K1 is Asn (SEQ ID NO:41),
then one or more of A1 to K1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy;
c) 1A1-X-Asn-Thr-5Ala-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E1- 20F1-G1-Asn-H1-Gly-25Pro-I1-Leu-Pro-Pro-30Thr-J1-Val-Gly-Ser-35Asn-Thr-Tyr-Z (SEQ ID NO:45)
wherein
A1 is Lys, Ala, Ser or hydrogen;
B1 is Ala, Ser or Thr;
C1 is Val, Leu or Ile;
D1 is His or Arg;
E1 is Ser or Thr;
F1 is Ser, Thr, Gln or Asn;
G1 is Asn, Gln or His;
H1 is Phe, Leu or Tyr;
I1 is Ile, Val, Ala or Leu
J1 is Asn, Asp or Gln; and
X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy;
provided that when
A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Val and J1 is Asn (SEQ ID NO:41),
then one or more of A1 to J1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and
d) 1A1-X-Asn-Thr-5Ala-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1- D1-E1-20F1-G1Asn-H1-Gly-25I1-J1-Leu-K1-L1-30Thr-M1-Val-Gly-Ser-35Asn-Thr- Tyr-Z (SEQ ID NO:31)
wherein
A1 is Lys, Ala, Ser, Hydrogen or acetylated Lys;
B1 is Ala, Ser or Thr;
C1 is Val, Leu or Ile;
D1 is His or Arg;
E1 is Ser or Thr;
F1 is Ser, Thr, Gln or Asn;
G1 is Asn, Gln or His;
H1 is Phe, Leu, or Tyr,
I1 is Ala or Pro;
J1 is Ile, Val, Ala, or Leu;
K1 is Ser, Pro, Leu, Ile or Thr;
L1 is Ser, Pro or Thr;
M1 is Asn, Asp or Gln;
X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is an amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, arlyoxy or aralkyloxy;
provided that
(a) when A1 is Lys, B1 is Ala, C1 is Val, D1 is His, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Phe, I1 is Ala, J1 is Ile, K1 is Ser, and M1 is Asn (SEQ ID NO:46);
(b) when A1 is Lys, B1 is Ala, C1 is Ile, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Ala, J1 is Ile, K1 is Ser, L1 is Pro, and M1 is Asn (SEQ ID NO:47);
(c) when A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Thr, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Ala, J1 is Ile, K1 is Ser, L1 is Pro, and M1 is Asn (SEQ ID NO:48);
(d) when A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Pro, J1 is Val, K1 is Pro, L1 is Pro, and M1 is Asn (SEQ ID NO:41);
(e) when A1 is Lys, B1 is Ala, C1 is Val, D1 is His, E1 is Ser, F1 is Asn, G1 is Asn, H1 is Leu, I1 is Pro, J1 is Val, K1 is Ser, L1 is Pro and M1 is Asn (SEQ ID NO:43); or
(f) when A1 is Lys, B1 is Thr, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is His, H1 is Leu, I1 is Ala, J1 is Ala, K1 is Leu, L1 is Pro and M1 is Asp (SEQ ID NO:49);
then one or more of any of A1 to M1 is not an L-amino acid and Z is not amino.

### Claim 2

The method of calim 1 wherein the amylin agonist analogue has the following amino acid sequence:
1A1-X-Asn-Thr-5Ala-Thr-Y-Ala-Thr10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E120F1- G1—Asn-H1Gly-25Pro-I1-Leu-Pro-J1-30Thr-K1-Val-Gly-Ser-35Asn-Thr—Tyr-Z (SEQ ID NO:40) wherein
A1 is Lys, Ala, Ser or Hydrogen;
B1 is Ala, Ser or Thr;
C1 is Val Leu or Ile;
D1 is His or Arg;
E1 is Ser or Thr;
F1 is Ser, Thr, Gln or Asn;
G1 is Asn, Gln or His;
H1 is Phe, Leu or Tyr;
I1 is Ile, Val, Ala or Leu;
J1 is Ser, Pro or Thr;
K1 is Asn, Asp or Gln;
X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thieother linkage; and Z is an amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Val, J1 is Pro, and K1 is Asn; then one or more A1 to K1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.

### Claim 3 (depends on 1)

The method of claim 1 wherein the amylin agonist analogue has the following amino acid sequence:
1A1—X—Asn—Thr—5Ala—Thr—Y—Ala—Thr—10Gln—Arg'Leu—B1—Asn—15Phe—Leu—C1—D1—E120F1—G1—Asn—H1—Gly—25Pro—I1—Leu—J1—Pro—30Thr—K1—Val—Gly—Ser—35Asn—Thr—Tyr—Z (SEQ ID NO:42)
wherein
A1 is Lys, Ala, Ser or hydrogen;
B1 is Ala, Ser or Thr;
C1 is Val, Leu, or Ile;
D1 is His or Arg;
E1 is Ser or Thr;
F1 is Ser, Thr, Gln or Asn;
G1 is Asn, Gln or His;
H1 is Phe, Leu or Tyr;
I1 is Ile, Val, Ala or Leu;
J1 is Ser, Pro, Leu, Ile or Thr;
K1 is Asn, Asp or Gln;
X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disfulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy, and provided that when
(a) A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Val, J1 is Pro and K1 is Asn; or
(b) A1 is Lys, B1 is Ala, C1 is Val, D1 is His, E1 is Ser, F1 is Asn, G1 is Asn, H1 is Leu, I1 is Val, J1 is Ser and K1 is Asn;
then one or more of A1 to K1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.

### Claim 4 (depends on 1)

The method of claim 1 wherein the amylin agonist analogue has the following amino acid sequence:
1A1-X-Asn-Thr-5Ala-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E1-20F1- G1-Asn-H1-Gly-25I1-J1-Leu-Pro-Pro-30-Thr-K1-Val-Gly-Ser-35Asn-Thr-Tyr-Z (SEQ ID NO:44)
where
A1 is Lys, Ala, Ser or hydrogen;
B1 is Ala, Ser or Thr;
C1 is Val, Leu or Ile;
D1 is His or Arg;
E1 is Ser or Thr;
F1 is Ser, Thr, Gln or Asn;
G1 is Asn, Gln or His;
H1 is Phe, Leu or Tyr;
I1 is Ala or Pro;
J1 is Ile, Val, Ala or Leu;
K1 is Asn, Asp or Gln;
X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Pro, J1 is Val and K1 is Asn (SEQ ID NO:41); then one or more of A1 to K1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.

### Claim 5 (depends on 1)

The method of claim 1 wherein the amylin agonist analogue has the following amino acid sequence:
1A1-X-Asn-Thr-5Ala-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E1-20F1- G1-Asn-H1-Gly-25Pro-I1-Leu-Pro-Pro-30Thr-J1-Val-Gly-Ser-35Asn-Thr-Tyr-Z (SEQ ID NO:45)
wherein
A1 is Lys, Ala, Ser or hydrogen;
B1 is Ala, Ser or Thr;
C1 is Val, Leu or Ile;
D1 is His or Arg;
E1 is Ser or Thr;
F1 is Ser, Thr, Gln or Asn;
G1 is Asn, Gln, or His;
H1 is Phe, Leu or Tyr;
I1 is Ile, Val, Ala or Leu
J1 is Asn, Asp or Gln;
X and Y are independently selected residues having side chains where are chemically bonded to each other to from an intramolecular linkage wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that when A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Val and J1 is Asn (SEQ ID NO:41); then one or more of A1 to J1 is a D-amino acid and Z is selected from the group consisting of alkylamino, dialylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy.

### Claim 6 (depends on 1)

The method of claim 1 wherein said amylin agonist analogue is any one of 18Arg25,28Pro—h-amylin (SEQ ID NO:3), des-1Lys18Arg25,28Pro-h-amylin (SEQ ID NO:6), 25,28,29Pro-h-amylin (SEQ ID NO:1), des-1Lys25,28,29Pro-h-amylin (SEQ ID NO:10), 18Arg25,28,29Pro-h-amylin (SEQ ID NO:8), des-1Lys18Arg25,28,29Pro-h-amylin (SEQ ID NO:9), 25Pro26Val28,29Pro-h-amylin (SEQ ID NO:7), or des-1Lys25Pro26Val28,29Pro-h-amylin (SEQ ID NO:38).

### Claim 7 (depends on 1)

The method of claim 1 wherein the amylin agonist analogue is 25,28,29Pro-h-amylin (SEQ ID NO:1).

### Claim 8 (depends on 1)

The method of claim 1 wherein the mammal has diabetes.

### Claim 9 (depends on 8)

The method of claim 8 wherein the diabetes is type 1.

### Claim 10 (depends on 8)

The method of claim 8 wherein the diabetes is type 2.

### Claim 11 (depends on 2)

The method of claim 2 wherein the mammal has diabetes.

### Claim 12 (depends on 11)

The method of claim 11 wherein the diabetes is type 1.

### Claim 13 (depends on 11)

The method of claim 11 wherein the diabetes is type 2.

### Claim 14 (depends on 3)

The method of claim 3 wherein the mammal has diabetes.

### Claim 15 (depends on 14)

The method of claim 14 wherein the diabetes is type 1.

### Claim 16 (depends on 14)

The method of claim 14 wherein the diabetes is type 2.

### Claim 17 (depends on 4)

The method of claim 4 wherein the mammal has diabetes.

### Claim 18 (depends on 17)

The method of claim 17 wherein the diabetes is type 1.

### Claim 19 (depends on 17)

The method of claim 17 wherein the diabetes is type 2.

### Claim 20 (depends on 17)

The method of claim 17 wherein the mammal has diabetes.

### Claim 21 (depends on 20)

The method of claim 20 wherein the diabetes is type 1.

### Claim 22 (depends on 20)

The method of claim 20 wherein the diabetets is type 2.

### Claim 23 (depends on 20)

The method of claim 20 wherein the mammal has diabetes.

### Claim 24 (depends on 23)

The method of claim 23 wherein the diabetes is type 1.

### Claim 25 (depends on 23)

The method of claim 23 wherein the diabetes is type 2.

### Claim 26 (depends on 23)

The method of claim 23 wherein the amylin agonist analogue has the following amino acid sequence:
1A1-X-Asn-Thr-Y-Ala-Thr-10Gln-Arg-Leu-B1-Asn-15Phe-Leu-C1-D1-E1- 20F1-G1Asn-H1-Gly-25I1-J1-Leu-K1-L1-30Thr-M1-Val-Gly-Ser-35Asn-Thr-Tyr-Z (SEQ ID NO:31)
wherein
A1 is Lys, Ala, Ser, Hydrogen or acetylated Lys;
B1 is Ala, Ser or Thr;
C1 is Val, Leu or Ile;
D1 is His or Arg;
E1 is Ser or Thr;
F1 is Ser, Thr, Gln or Asn;
G1 is Asn, Gln or His;
H1 is Phe, Leu or Tyr,
I1 is Ala or Pro;
J1 is Ile, Val, Ala or Leu;
K1 is Ser, Pro, Leu, Ile or Thr;
L1 is Ser, Pro or Thr;
M1 is Asn, Asp or Gln;
X and Y are independently selected residues having side chains which are chemically bonded to each other to form an intramolecular linkage, wherein said intramolecular linkage comprises a disulfide bond, a lactam or a thioether linkage; and Z is an amino, alkylamino, dialkylamino, cycloalkylamino, arylamino, aralkylamino, alkyloxy, aryloxy or aralkyloxy; and provided that
(a) when A1 is Lys, B1 is Ala, C1 is Val, D1 is His, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Phe, I1 is Ala, J1 is Ile, K1 is Ser, L1 is Ser, and M1 is Asn (SEQ ID NO:46);
(b) when A1 is Lys, B1 is Ala, C1 is Ile, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, L1 is Ala, J1 is Ile, K1 is Ser, L1 is Pro, and M1 is Asn (SEQ ID NO:47);
(c) when A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Thr, F1 is Ser, G1 is Asn, H1 is Leu, L1 is Ala, J1 is Ile, K1 is Ser, L1 is Pro, and M1 is Asn (SEQ ID NO:48);
(d) when A1 is Lys, B1 is Ala, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is Asn, H1 is Leu, I1 is Pro, J1 is Val, K1 is Pro, L1 is Pro, and M1 is Asn (SEQ ID NO:41);
(e) when A1 is Lys, B1 is Ala, C1 is Val, D1 is His, E1 is Ser, F1 is Asn, G1 is Asn, H1 is Leu, I1 is Pro, J1 is Val, K1 is Ser, L1 is Pro and M1 is Asn (SEQ ID NO:43); or
(f) when A1 is Lys, B1 is Thr, C1 is Val, D1 is Arg, E1 is Ser, F1 is Ser, G1 is His, H1 is Leu, I1 is Ala, J1 is Ala, K1 is Leu, L1 is Pro and M1 is Asp (SEQ ID NO:49);
then one or more of any of A1 to M1 is not an L-amino acid and Z is not amino.

### Claim 27 (depends on 26)

The method of claim 26 wherein the mammal has diabetes.

### Claim 28 (depends on 27)

The method of claim 27 wherein the diabetes is type 1.

### Claim 29 (depends on 27)

The method of claim 27 wherein the diabetes is type 2.