# US 10,308,699 B2 · Peptidomimetic macrocycles

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- Number: US 10,308,699 B2
- Document ID: US10308699B2
- Status: Granted
- Kind: B2
- Application number: 15/332,492
- Filed: 2016-10-24
- Published: 2017-08-10
- Granted: 2019-06-04
- Earliest claimed: 2011-10-18
- Assignees: Aileron Therapeutics, Inc.
- Applicants: Aileron Therapeutics, Inc.
- Inventors: Noriyuki Kawahata; Vincent Guerlavais; Manoj Samant
- Web page: https://patentgrep.com/patent/US10308699B2

## CPC

- C07K 14/60: Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/02: Nutrients, e.g. vitamins, minerals
- A61P 3/04: Anorexiants; Antiobesity agents
- A61P 5/00: Drugs for disorders of the endocrine system
- A61P 5/02: of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
- A61P 5/06: of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
- A61P 5/10: of the posterior pituitary hormones, e.g. oxytocin, ADH
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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)

## Abstract

The present invention provides peptidomimetic macrocycles capable of modulating growth hormone levels and methods of using such macrocycles for the treatment of disease.

## Claims

### Claim 1

A method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least about 60% identical to GHRH 1-29, wherein the peptidomimetic macrocycle comprises at least two macrocycle-forming linkers, wherein the first of the at least two macrocycle-forming linkers connects a first amino acid to a second amino acid, and the second of the at least two macrocycle-forming linkers connects a third amino acid to a fourth amino acid, wherein the peptidomimetic macrocycle comprises an α,α-disubstituted amino acid, wherein the peptidomimetic macrocycle comprises a helix.

### Claim 2 (depends on 1)

The method of claim 1, wherein the amino acid sequence of the peptidomimetic macrocycle is at least about 60% identical to an amino acid sequence chosen from the group consisting of SEQ ID NO. 2-180.

### Claim 3 (depends on 1)

The method of claim 1, wherein the amino acid sequence of said peptidomimetic macrocycle is at least about 80% identical to an amino acid sequence chosen from the group consisting of SEQ ID NO. 2-180.

### Claim 4 (depends on 1)

The method of claim 1, wherein the amino acid sequence of said peptidomimetic macrocycle is at least about 90% identical to an amino acid sequence chosen from the group consisting of SEQ ID NO. 2-180.

### Claim 5 (depends on 1)

The method of claim 1, wherein the amino acid sequence of said peptidomimetic macrocycle is chosen from the group consisting of SEQ ID NO. 2-180.

### Claim 6 (depends on 1)

The method of claim 1, wherein the peptidomimetic macrocycle comprises an α-helix.

### Claim 7 (depends on 1)

The method of claim 1, wherein the condition is a cachexia.

### Claim 8 (depends on 1)

The method of claim 1, wherein the condition is a lipodystrophy.

### Claim 9 (depends on 1)

The method of claim 1, wherein the condition is a growth hormone disorder.

### Claim 10 (depends on 1)

The method of claim 1, wherein each of the at least two macrocycle-forming linkers connects a pair of amino acids corresponding to one of the following locations of amino acids: 4 and 8; 5 and 12; 8 and 12; 8 and 15; 9 and 16; 12 and 16; 12 and 19; 15 and 22; 18 and 25; 21 and 25; 21 and 28; 22 and 29; or 25 and 29 of GHRH 1-29.

### Claim 11 (depends on 1)

The method of claim 1, wherein each of the at least two macrocycle-forming linkers connects a pair of amino acids corresponding to one of the following locations of amino acids: 4 and 8; 5 and 12; 12 and 19; 15 and 22; 18 and 25; 21 and 25; or 21 and 28 of GHRH 1-29.

### Claim 12 (depends on 1)

The method of claim 1, wherein the first macrocycle-forming linker connects a pair of amino acids corresponding to one of the following locations of amino acids: 4 and 8; 5 and 12; 8 and 12; 8 and 15; 9 and 16; 12 and 16; or 12 and 19 of GHRH 1-29; and the second macrocycle-forming linker connects a pair of amino acids corresponding to one of the following locations of amino acid 15 and 22; 18 and 25; 21 and 25; 21 and 28; 22 and 29; or 25 and 29 of GHRH 1-29.

### Claim 13 (depends on 1)

The method of claim 1, wherein the first macrocycle-forming linker connects a pair of amino acids corresponding to one of the following locations of amino acids: 4 and 8; 5 and 12; 8 and 12; or 12 and 19 of GHRH 1-29; and the second macrocycle-forming linker connects a pair of amino acids corresponding to one of the following locations of amino acid 15 and 22; 18 and 25; 21 and 25; or 21 and 28 of GHRH 1-29.

### Claim 14 (depends on 1)

The method of claim 1, wherein the first macrocycle-forming linker connects a pair of amino acids corresponding to amino acids locations 4 and 8 of GHRH 1-29.

### Claim 15 (depends on 1)

The method of claim 1, wherein the second macrocycle-forming linker connects a pair of amino acids corresponding to amino acid locations 21 and 25 of GHRH 1-29.

### Claim 16 (depends on 1)

The method of claim 1, wherein the first macrocycle-forming linker connects a pair of amino acids corresponding to amino acid locations 4 and 8 of GHRH 1-29; and the second macrocycle-forming linker connects a pair of amino acids corresponding to amino acid locations 21 and 25 of GHRH 1-29.

### Claim 17 (depends on 1)

The method of claim 1, wherein each amino acid connected by the at least two macrocycle-forming linkers is an α,α-disubstituted amino acid.

### Claim 18 (depends on 1)

The method of claim 1, wherein the peptidomimetic macrocycle has the formula:
wherein:
each A, C, D, and E is independently an amino acid;
B is an amino acid or
L is a macrocycle-forming linker of the formula -L1-L2-;
and wherein A, B, C, D, and E, taken together with the crosslinked amino acids connected by the macrocycle-forming linker L, form the amino acid sequence of the peptidomimetic macrocycle;
R1 and R2 are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;
R3 is hydrogen, alkyl, alkenyl, alkynyl, arylalkyl, heteroalkyl, cycloalkyl, heterocycloalkyl, cycloalkylalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5;
L1 and L2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4-]n, each being optionally substituted with R5;
each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each K is O, S, SO, SO2, CO, CO2, or CONR3;
each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SOR6, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent;
each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent;
R7 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;
R8 is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
v and w are independently integers from 1-100;
u is an integer from 1 to 3;
x, y and z are independently integers from 0-10; and
n is an integer from 1-5.

### Claim 19 (depends on 18)

The method of claim 18, wherein L1 and L2 are independently alkylene, alkenylene or alkynylene.

### Claim 20 (depends on 18)

The method of claim 18, wherein L1 and L2 are independently C3-C10 alkylene or alkenylene.

### Claim 21 (depends on 18)

The method of claim 18, wherein L1 and L2 are independently C3-C6 alkylene or alkenylene.

### Claim 22 (depends on 18)

The method of claim 18, wherein R1 and R2 are independently H.

### Claim 23 (depends on 18)

The method of claim 18, wherein R1 and R2 are independently alkyl.

### Claim 24 (depends on 18)

The method of claim 18, wherein R1 and R2 are independently methyl.

### Claim 25 (depends on 18)

The method of claim 18, wherein one of R1 and R2 is —H, and the other of R1 and R2 is alkyl.

### Claim 26 (depends on 18)

The method of claim 18, wherein the sum of x+y+z is 2, 3, or 6.

### Claim 27 (depends on 18)

The method of claim 18, wherein each of v and w is independently an integer from 1 to 25.

### Claim 28 (depends on 18)

The method of claim 18, wherein A, B, C, D, and E, taken together with the crosslinked amino acids connected by the macrocycle-forming linker L, form an amino acid sequence which is at least about 60% identical to GHRH 1-29.

### Claim 29 (depends on 18)

The method of claim 18, wherein u is 2.

### Claim 30 (depends on 29)

The method of claim 29, wherein the peptidomimetic macrocycle has the formula:
wherein each A, C, D, and E is independently an amino acid;
B is an amino acid or
L′ is a macrocycle-forming linker of the formula -L1′-L2′-;
and wherein A, B, C, D, and E, taken together with the crosslinked amino acids connected by the macrocycle-forming linkers L and L′, form the amino acid sequence of the peptidomimetic macrocycle;
R1′ and R2′ are independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, or heterocycloalkyl, unsubstituted or substituted with halo-;
L1′ and L2′ are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4-]n, each being optionally substituted with R5;
each K is independently O, S, SO, SO2, CO, CO2, or CONR3;
R7′ is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with a D residue;
R8′ is —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkyl, heteroalkyl, cycloalkylalkyl, heterocycloalkyl, cycloaryl, or heterocycloaryl, optionally substituted with R5, or part of a cyclic structure with an E residue;
v′ and w′ are independently integers from 1-100;
x′, y′ and z′ are independently integers from 0-10; and
n is an integer from 1-5.

### Claim 31 (depends on 30)

The method of claim 30, wherein the sum of x′+y′+z′ is 2, 3, or 6.

### Claim 32 (depends on 1)

The method of claim 1, wherein the condition is a muscle wasting disease.

### Claim 33 (depends on 1)

The method of claim 1, wherein the condition is a growth hormone deficiency.

### Claim 34 (depends on 1)

The method of claim 1, wherein the condition is gastroparesis.

### Claim 35

A method of treating a condition in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises an amino acid sequence of formula:
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10-X11-X12-X13-X14-X15-X16-X17-X18-X19-X20-X21-X22-X23-X24-X25-X26-X27-X28-X29 (SEQ ID NO: 1)
wherein:
X1 is Tyr or His;
X2 is Ala, D-Ala, or Val;
X3 is Asp;
X4 is Ala or a crosslinked amino acid;
X5 is Ile;
X6 is Phe;
X7 is Thr;
X8 is Gln, Asn, or a crosslinked amino acid;
X9 is Ser or a crosslinked amino acid;
X10 is Tyr;
X11 is Arg, Ala or Gln;
X12 is Lys, Ala, Gln or a crosslinked amino acid;
X13 is Val or Ile;
X14 is Leu;
X15 is Gly, Ala or a crosslinked amino acid;
X16 is Gln, Glu or a crosslinked amino acid;
X17 is Leu;
X18 is Ser, Tyr or a crosslinked amino acid;
X19 is Ala or a crosslinked amino acid;
X20 is Arg or Gln;
X21 is Lys, Gln or a crosslinked amino acid;
X22 is Leu, Ala, or a crosslinked amino acid;
X23 is Leu;
X24 is Gln, Glu or His;
X25 is Asp, Glu or a crosslinked amino acid;
X26 is Ile;
X27 is Met, Ile, Leu or Nle;
X28 is Ser or a crosslinked amino acid;
X29 is Arg, Ala, Gln or a crosslinked amino acid;
wherein at least one of the crosslinked amino acids is an α,α-disubstituted amino acid;
wherein the peptidomimetic macrocycle comprises at least one macrocycle-forming linker connecting at least one pair of amino acids selected from X1-X29;
L is a macrocycle-forming linker of the formula -L1-L2-;
L1 and L2 are independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—R4—K—R4-]n, each being optionally substituted with R5, wherein n is an integer from 1-5;
each R4 is alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
each K is O, S, SO, SO2, CO, or CO2;
each R5 is independently halogen, alkyl, —OR6, —N(R6)2, —SR6, —SORE, —SO2R6, —CO2R6, a fluorescent moiety, a radioisotope or a therapeutic agent; and
each R6 is independently —H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent.

### Claim 36 (depends on 35)

The method of claim 35, wherein the at least one macrocycle-forming linker connects one of the following pairs of amino acids: X4 and X8; X5 and X12; X8 and X12; X8 and X15; X9 and X16; X12 and X16; X12 and X19; X15 and X22; X18 and X25; X21 and X25; X21 and X28; X22 and X29; or X25 and X29.

### Claim 37 (depends on 35)

The method of claim 35, wherein the at least one macrocycle-forming linker connects one of the following pairs of amino acids: X4 and X8; X5 and X12; X12 and X19; X15 and X22; X18 and X25; X21 and X25; or X21 and X28.

### Claim 38 (depends on 35)

The method of claim 35, wherein the condition is a muscle wasting disease.

### Claim 39 (depends on 35)

The method of claim 35, wherein the condition is a growth hormone deficiency.

### Claim 40 (depends on 35)

The method of claim 35, wherein the condition is gastroparesis.

### Claim 41 (depends on 35)

The method of claim 35, wherein the condition is a cachexia.

### Claim 42 (depends on 35)

The method of claim 35, wherein the condition is a lipodystrophy.

### Claim 43 (depends on 35)

The method of claim 35, wherein the condition is a growth hormone disorder.