Peptidomimetic macrocycles
First Claim
Patent Images
1. A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to GHRH 1-29, and a crosslinker that is a macrocycle-forming linker of the formula -L1-L2-, wherein:
- each L1 and L2 is 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, or CO2;
each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene;
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; and
each n is independently an integer from 1-5, wherein the peptidomimetic macrocycle comprises an α
,α
-disubstituted amino acid.
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Accused Products
Abstract
The present invention provides peptidomimetic macrocycles capable of modulating growth hormone levels and methods of using such macrocycles for the treatment of disease.
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Citations
56 Claims
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1. A peptidomimetic macrocycle comprising an amino acid sequence which is at least about 60% identical to GHRH 1-29, and a crosslinker that is a macrocycle-forming linker of the formula -L1-L2-, wherein:
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each L1 and L2 is 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, or CO2; each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; 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; and
each n is independently an integer from 1-5, wherein the peptidomimetic macrocycle comprises an α
,α
-disubstituted amino acid. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21)
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22. 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, and a crosslinker that is a macrocycle-forming linker of the formula -L1-L2-, wherein:
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each L1 and L2 is 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, or CO2; each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; 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; andeach n is independently an integer from 1-5, wherein the peptidomimetic macrocycle comprises an α
,α
-disubstituted amino acid. - View Dependent Claims (23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50)
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51. 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, comprising at least two macrocycle-forming linkers, wherein the first of said two macrocycle-forming linkers connects a first amino acid to a second amino acid, and the second of said 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.
- ,α
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52. 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:
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i) an amino acid sequence which is at least about 60% identical to GHRH 1-29; and ii) a macrocycle-forming linker connecting a first amino acid to a second amino acid, wherein the peptidomimetic macrocycle comprises an α
,α
-disubstituted amino acid, and wherein the first and second amino acids are selected from amino acids corresponding to 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; and
22 and 29 of GHRH 1-29.
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53. 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:
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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-X29wherein; 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 the peptidomimetic macrocycle comprises at least one macrocycle-forming linker L connecting at least one pair of amino acids; each L is independently a macrocycle-forming linker of the formula -L1-L2-; each L1 and L2 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—
R4—
K—
R4—
]n, each being optionally substituted with R5;each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently O, S, SO, SO2, CO, or CO2; 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; andeach n is independently an integer from 1-5, wherein the peptidomimetic macrocycle comprises an α
,α
-disubstituted amino acid.
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54. A pharmaceutical composition comprising a peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises an amino acid sequence which is at least about 60% identical to GHRH 1-29, comprising at least two macrocycle-forming linkers, wherein the first of said two macrocycle-forming linkers connects a first amino acid to a second amino acid, and the second of said 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.
- ,α
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55. A pharmaceutical composition comprising a peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises:
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i) an amino acid sequence which is at least about 60% identical to GHRH 1-29; and ii) a macrocycle-forming linker connecting a first amino acid to a second amino acid, wherein the peptidomimetic macrocycle comprises an α
,α
-disubstituted amino acid, and wherein the first and second amino acids are selected from amino acids corresponding to 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; and
22 and 29 of GHRH 1-29.
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56. A pharmaceutical composition comprising a peptidomimetic macrocycle, wherein the peptidomimetic macrocycle comprises an amino acid sequence of formula:
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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-X29wherein; 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 the peptidomimetic macrocycle comprises at least one macrocycle-forming linker L connecting at least one pair of amino acids; each L is independently a macrocycle-forming linker of the formula -L1-L2-; each L1 and L2 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, cycloarylene, heterocycloarylene, or [—
R4—
K—
R4—
]n, each being optionally substituted with R5;each R4 is independently alkylene, alkenylene, alkynylene, heteroalkylene, cycloalkylene, heterocycloalkylene, arylene, or heteroarylene; each K is independently O, S, SO, SO2, CO, or CO2; 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; andeach n is independently an integer from 1-5, wherein the peptidomimetic macrocycle comprises an α
,α
-disubstituted amino acid.
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Specification