Peptidomimetic macrocycles
First 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.
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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
43 Claims
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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. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)
- ,α
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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:
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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-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; andeach R6 is independently —
H, alkyl, alkenyl, alkynyl, arylalkyl, cycloalkylalkyl, heterocycloalkyl, a fluorescent moiety, a radioisotope or a therapeutic agent. - View Dependent Claims (36, 37, 38, 39, 40, 41, 42, 43)
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Specification