Growth Hormone Releasing Peptides
AssigneeIpsen Pharma S.A.S.
InventorZheng Xin DONG
Life of this patent
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Abstract
Disclosed are peptide and peptidomimetic compounds generally according to formula (I) that are useful as GHRP analogs: R1-A1-A2-A3-A4-A5-R2 (I) wherein: A1 is Aib, Apc or Inp; A2 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp; A3 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp; A4 is 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl); A5 is Apc, Dab, Dap, Lys, Orn, or deleted; R1 is hydrogen, (C1-6)alkyl, (C5-14)aryl, (C1-6)alkyl(C5-14)aryl, (C3-8)cycloakyl, or (C2-10)acyl; and R2 is OH or NH2; and pharmaceutical compositions and methods of use thereof.
Claims40
A compound according to formula (I):
- R1-A1-A2-A3-A4-A5-R2 (I)
- or a pharmaceutically acceptable salt thereof, wherein:
- A1 is Aib, Apc or Inp;
- A2 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp;
- A3 is D-Bal, D-Bip, D-Bpa, D-Dip, D-1Nal, D-2Nal, D-Ser(Bzl), or D-Trp;
- A4 is 2Fua, Orn, 2Pal, 3Pal, 4Pal, Pff, Phe, Pim, Taz, 2Thi, 3Thi, Thr(Bzl);
- A5 is Apc, Dab, Dap, Lys, Orn, or deleted;
- R1 is hydrogen, (C1-6)alkyl, (C5-14)aryl, (C1-6)alkyl(C5-14)aryl, (C3-8)cycloakyl, or (C2-10)acyl;
- and
- R2 is OH or NH2;
- provided that:
- when A5 is Dab, Dap, Lys, or Orn, then:
- A2 is D-Bip, D-Bpa, D-Dip or D-Bal;
- or
- A3 is D-Bip, D-Bpa, D-Dip or D-Bal;
- or
- A4 is 2Thi, 3Thi, Taz, 2Fua, 2Pal, 3Pal, 4Pal, Orn, Thr(Bzl), or Pff;
- when A5 is deleted, then:
- A3 is D-Bip, D-Bpa, or D-Dip;
- or
- A4 is 2Fua, Pff, Taz, or Thr(Bzl);
- or
- A1 is Apc and—
- A2 is D-Bip, D-Bpa, D-Dip or D-Bal;
- or
- A3 is D-Bip, D-Bpa, D-Dip or D-Bal;
- or
- A4 is 2Thi, 3Thi, Orn, 2Pal, 3Pal, or 4Pal;
A compound according to the formula:
- H-Inp-D-1Nal-D-Trp-2Thi-Apc-NH2;
- H-Inp-D-Bal-D-Trp-2Thi-Apc-NH2;
- H-Apc-D-1Nal-D-Trp-2Thi-Apc-NH2;
- H-Apc-D-Bal-D-Trp-2Thi-Apc-NH2;
- or
- H-Apc-D-1Nal-D-Trp-Phe-Lys-NH2;
- or a pharmaceutically acceptable salt thereof.
A method of determining a compound's ability to bind to a GHS receptor, said method comprising the step of measuring the ability of a compound to affect binding of a compound according to formula (I), Group 1, Group 1A, Group 2, Group 2A, Group 2B, Group 2B-1, Group 2B-1a, Group 2B-1b, Group 2B-1c, Group 2B-1d, Group 2B-2, Group 2B-2a, Group 2C, or Group 2C-1 to said receptor, to a fragment of said receptor, to a polypeptide comprising said fragment of said receptor, or to a derivative of said polypeptide.
A method for achieving a beneficial affect in a subject in a subject in need thereof, said method comprising the step of administering to said subject an effective amount of a compound according to formula (I), Group 1, Group 1A, Group 2, Group 2A, Group 2B, Group 2B-1, Group 2B-1a, Group 2B-1b, Group 2B-1c, Group 2B-1d, Group 2B-2, Group 2B-2a, Group 2C, or Group 2C-1, or a pharmaceutically acceptable salt thereof, wherein said effective amount is effective for producing a beneficial effect in helping to treat (e.g., cure or reduce the severity) or prevent (e.g., reduce the likelihood of onset or severity) a disease or disorder.
A method for stimulating growth hormone secretion in a subject in need of such stimulation, comprising the step of administering to a subject an effective amount of a ghrelin agonist according to formula (I), Group 1, Group 1A, Group 2, Group 2A, Group 2B, Group 2B-1, Group 2B-1a, Group 2B-1b, Group 2B-1c, Group 2B-1d, Group 2B-2, Group 2B-2a, Group 2C, or Group 2C-1, or a pharmaceutically acceptable salt thereof, wherein said effective amount is at least an amount sufficient to produce a detectable increase in growth hormone secretion and, preferably, is an amount sufficient to achieve a beneficial affect in a patient.
A method for suppressing growth hormone secretion in a subject in need of such suppression, comprising the step of administering to a subject an effective amount of a ghrelin antagonist according to formula (I), Group 1, Group 1A, Group 2, Group 2A, Group 2B, Group 2B-1, Group 2B-1a, Group 2B-1b, Group 2B-1c, Group 2B-1d, Group 2B-2, Group 2B-2a, Group 2C, or Group 2C-1, or a pharmaceutically acceptable salt thereof, wherein said effective amount is at least an amount sufficient to produce a detectable decrease in growth hormone secretion and, preferably, is an amount sufficient to achieve a beneficial affect in a patient.
A method of eliciting a ghrelin agonist effect in a subject, comprising the step of administering to a subject an effective amount of a ghrelin agonist according to formula (I), Group 1, Group 1A, Group 2, Group 2A, Group 2B, Group 2B-1, Group 2B-1a, Group 2B-1b, Group 2B-1c, Group 2B-1d, Group 2B-2, Group 2B-2a, Group 2C, or Group 2C-1, or a pharmaceutically acceptable salt thereof, wherein said effective amount is at least an amount sufficient to produce a detectable increase in growth hormone secretion and, preferably, is an amount sufficient to achieve a beneficial affect in a patient.
A method of eliciting a ghrelin antagonist effect in a subject, comprising the step of administering to a subject an effective amount of a ghrelin antagonist according to formula (I), Group 1, Group 1A, Group 2, Group 2A, Group 2B, Group 2B-1, Group 2B-1a, Group 2B-1b, Group 2B-1c, Group 2B-1d, Group 2B-2, Group 2B-2a, Group 2C, or Group 2C-1, or a pharmaceutically acceptable salt thereof, wherein said effective amount is at least an amount sufficient to produce a detectable decrease in growth hormone secretion and, preferably, is an amount sufficient to achieve a beneficial affect in a patient.
A method of achieving a beneficial cardiovascular effect in a subject in need thereof, comprising the step of administering to a subject an effective amount of a ghrelin agonist according to formula (I), Group 1, Group 1A, Group 2, Group 2A, Group 2B, Group 2B-1, Group 2B-1a, Group 2B-1b, Group 2B-1c, Group 2B-1d, Group 2B-2, Group 2B-2a, Group 2C, Group 2C-1 or Group 3, or a pharmaceutically acceptable salt thereof, wherein said effective amount is at least an amount sufficient to produce a beneficial affect in said subject.
Dependencies are inferred from the claim text.