US 7,452,865 B2Granted

Antagonistic analogs of GH RH (2003)

AssigneesThe Administrare's of the Tulane Educational Fund, United States of America by Dept of Veterans Affairs

InventorsAndrew V. Schally, Jozsef Varga, Marta Zarandi, Ren Zhi Cai

Life of this patent

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Abstract

There is provided a novel series of synthetic antagonistic analogs of hGH-RH(1-29)NH2. These analogs inhibit the activity of endogenous hGH-RH on the pituitary GH-RH receptors, and therefore prevent the release of growth hormone. The analogs also inhibit the proliferation of human cancers through a direct effect on the cancer cells. The higher inhibitory potencies of the new analogs, as compared to previously described ones, results from replacement of various amino acids.

Claims11

Dependent claims

A peptide selected from the group having the formulae:

R1-A0-A1-A2-Asp-Ala-A5-A6-Thr-A8-A9-A10-A11-A12-Val-Leu-A15-A16-Leu-Ser-A19-A20-A21-A22-Leu-Gln-Asp-Ile-A27-A28-A29-A30-R2
wherein R1 is a member of the group consisting of a) PhAc, Hca, Dat, IndAc Ipa, 1-Nac, 2-Nac, 1-Npr, 2-Npr, Ibu;
CH3(CH2)nCO, or HOOC(CH2)nCO, where n is an integer from 2 to 20, and b) any other straight chain, branch chain, saturated, unsaturated or poly unsaturted aliphatic carboxyl group of 2-30 carbon atoms and any carbocyclic or heterocyclic aromatic carboxyl group of 3-8 carbon atoms containing at least one atom of the group S, N, and O in the hetercyclic ring,
A0 is Phe, D-Phe, Arg, D-Arg, or is absent
A1 is Tyr or His,
A2 is D-Arg or D-Cit,
A5 is Ile or Val,
A6 is Phe, Tyr, Nal, or Phe(Y), in which Y=F, Cl, Br, or I,
A8 is Asn, D-Asn, Cit, D-Cit, Gln, D-Gln, Ser, D-Ser, Thr, D-Thr, Ala, D-Ala, Abu, D-Abu or Aib,
A9 is His, D-His, Amp, D-Amp, Gup, or D-Gup,
A10 is Tyr, Tyr(Et), Tyr(Me);
Phe(Y), in which Y=H, F, Cl, Br, or I;
Amp, His, Cha, Chg, Bpa, Dip, Trp, Trp(For), Tpi, 1-Nal, 2-Nal, 3-Pal, 4-Pal, Phe(NH2), or Phe(NO2),
A11 is His, D-His, Arg, D-Arg, Cit Har, D-Har, Amp, D-Amp, Gup, or D-Gup,
A12 is Lys, D-Lys, Orn, D-Orn, Har, D-Har, Cit, D-Cit, Nle, or Ala,
A15 is Gly, Ala, Abu, Aib, Nle, Gln, Cit or His,
A16 is Gln or Arg,
A19 is Ala or Abu,
A20 is His, D-His, Arg, D-Arg, or Cit,
A21 is Lys, D-Lys, Orn, D-Orn, Cit, or D-Cit,
A22 is Leu, Ala or Aib,
A27 is Met, Leu, Nle, Abu, or D-Arg,
A28 is Arg, D-Arg, Har, D-Har, Ser, Asn, Asp, Ala, Abu, or Cit,
A29 is Arg, D-Arg, Har, D-Har, Cit D-Cit, or Agm,
A30 is Arg, D-Arg, Har, D-Har, Cit, D-Cit Agm, absent,
R2 is —NH2, —NH—NH2, —NH—OH, —NHR3, —NR3R4, —OH, or —OR3, in which R3 and R4 are any of C1-10 alkyl, C2-10 alkenyl, C2-10 alkinyl, C7-16 phenylalkyl, —C6H5, or —CH(C6H5)2;
provided that if A29 is Agm then A30 and R2 are absent, and if A30 is Agm then R2 is absent, and pharmaceutically acceptable salts thereof.

24 more elements

A compound selected from the group consisting of:

[CH3(CH2)4CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 2
[HOOC(CH2)4CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 3
[CH3(CH2)6CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 4
[HOOC(CH2)6CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 5
[CH3(CH2)8CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 6
[HOOC(CH2)8CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 7
[CH3(CH2)10CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 8
[HOOC(CH2)10CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 9
[CH3(CH2)12CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 10
[HOOC(CH2)12CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 11
[CH3(CH2)14CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 12
[HOOC(CH2)14CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 13
[CH3(CH2)6CO-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, Har28, D-Arg29]hGH-RH(1-29)NH2 Peptide 14
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, Har28, D-Arg29]hGH-RH(1-29)NH2 Peptide 15
[CH3(CH2)14CO-Phe0, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 16
[CH3(CH2)14CO-D-Phe0, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 17
[PhAc-Arg0, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 18
[PhAc-D-Arg0, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 19
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Cit8, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 21
[PhAc-Tyr1, D-Arg2, Phe(Cl)6, Cit8, Cit9, Abu15, Nle27, D-Arg27, Har29]hGH-RH(1-29)NH2 Peptide 22
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Cit8, Arg9, Abu15, Nle27, Har28, D-Arg29]hGH-RH(1-29)NH2 Peptide 23
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Cit8, Cit9, Abu15, Nle27, Har28, D-Arg29]hGH-RH(1-29)NH2 Peptide 24
[HOOC(CH2)12CO-Tyr1, D-Arg2, Phe(pCl)6, Cit8, Cit9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 25
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, D-Ala8, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 26
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Cit9, Abu15, Nle27, Har28, D-Arg29]hGH-RH(1-29)NH2 Peptide 28
[PhAC-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Amp10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 30
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Amp10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 31
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Arg9, His10, Abut15, Nle27, Arg28, Har29]hGH-RH(1-29)NH2 Peptide 32
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Cha10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 33
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tpi10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 34
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, 2-Nal10, Abu15, Nle27, D-Arg28, Har29 ]hGH-RH(1-29) NH2 Peptide 35
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Dip10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 36
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Phe(pNH2)10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 37
[PhAr-Tyr1, D-Arg2, Phe(pCl)6, Har9, Trp10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 38
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Phe(pNO2)10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 39
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, 3-Pal10, Abu15, Nle27, D-Arg28, Har29 ]hGH-RH(1-29)NH2 Peptide 40
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Et)10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 41
[PhAc-His1, D-Arg2, Tyr6, Har9, Bpa10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 42
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Har12, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 43
[Hca-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NHEt Peptide 45
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NHEt Peptide 46
[Hca-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NHEt Peptide 47
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NHEt Peptide 48
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Aib15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NHEt Peptide 49
[PhAC-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Orn12, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NHEt Peptide 50
[Hca-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg28, Agm29]hGH-RH(1-29) Peptide 51
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg28, Agm29]hGH-RH(1-29) Peptide 52
[Hca-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg28, Har29, Har30]hGH-RH(1-30)NH2 Peptide 53
[Dat-Tyr1, D-Arg2, Phe(pCl)5, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg28, Har29, Har30]hGH-RH(1-30)NH2 Peptide 54
[Ipa-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg-28, Har29, Har30]hGH-RH(1-30)NH2 Peptide 55
[Hca-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg28, Har29, Har30]hGH-RH(1-30)NHEt Peptide 56
[Hca-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg28, D-Arg29, Har30]hGH-RH(1-30)NH2 Peptide 57
[Hca-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg28, Har29, D-Arg30]hGH-RH(1-30)NH2 Peptide 58
[Hca-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg28, Har29, Agm30]hGH-RH(1-30) Peptide 59
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, Nle27, D-Arg28, Har29, Agm30]hGH-RH(1-30) Peptide 60
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, His11, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 62
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Har11, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 63
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Amp11, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 64
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Cit11, Abu15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 65
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, Abu15, His20, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 84
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Har9, Tyr(Me)10, His11, Abu15, His20, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 85
[PhAc-Tyr1, D-Arg2, Phe(pCl)6, Arg9, Cit15, Nle27, D-Arg28, Har29]hGH-RH(1-29)NH2 Peptide 90.

59 more elements

Dependencies are inferred from the claim text.

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Abstract

A peptide selected from the group having the formulae:

R1-A0-A1-A2-Asp-Ala-A5-A6-Thr-A8-A9-A10-A11-A12-Val-Leu-A15-A16-Leu-Ser-A19-A20-A21-A22-Leu-Gln-Asp-Ile-A27-A28-A29-A30-R2
wherein R1 is a member of the group consisting of a) PhAc, Hca, Dat, IndAc Ipa, 1-Nac, 2-Nac, 1-Npr, 2-Npr, Ibu;
CH3(CH2)nCO, or HOOC(CH2)nCO, where n is an integer from 2 to 20, and b) any other straight chain, branch chain, saturated, unsaturated or poly unsaturted aliphatic carboxyl group of 2-30 carbon atoms and any carbocyclic or heterocyclic aromatic carboxyl group of 3-8 carbon atoms containing at least one atom of the group S, N, and O in the hetercyclic ring,
A0 is Phe, D-Phe, Arg, D-Arg, or is absent
A1 is Tyr or His,
A2 is D-Arg or D-Cit,
A5 is Ile or Val,
A6 is Phe, Tyr, Nal, or Phe(Y), in which Y=F, Cl, Br, or I,
A8 is Asn, D-Asn, Cit, D-Cit, Gln, D-Gln, Ser, D-Ser, Thr, D-Thr, Ala, D-Ala, Abu, D-Abu or Aib,
A9 is His, D-His, Amp, D-Amp, Gup, or D-Gup,
A10 is Tyr, Tyr(Et), Tyr(Me);
Phe(Y), in which Y=H, F, Cl, Br, or I;
Amp, His, Cha, Chg, Bpa, Dip, Trp, Trp(For), Tpi, 1-Nal, 2-Nal, 3-Pal, 4-Pal, Phe(NH2), or Phe(NO2),
A11 is His, D-His, Arg, D-Arg, Cit Har, D-Har, Amp, D-Amp, Gup, or D-Gup,
A12 is Lys, D-Lys, Orn, D-Orn, Har, D-Har, Cit, D-Cit, Nle, or Ala,
A15 is Gly, Ala, Abu, Aib, Nle, Gln, Cit or His,
A16 is Gln or Arg,
A19 is Ala or Abu,
A20 is His, D-His, Arg, D-Arg, or Cit,
A21 is Lys, D-Lys, Orn, D-Orn, Cit, or D-Cit,
A22 is Leu, Ala or Aib,
A27 is Met, Leu, Nle, Abu, or D-Arg,
A28 is Arg, D-Arg, Har, D-Har, Ser, Asn, Asp, Ala, Abu, or Cit,
A29 is Arg, D-Arg, Har, D-Har, Cit D-Cit, or Agm,
A30 is Arg, D-Arg, Har, D-Har, Cit, D-Cit Agm, absent,
R2 is —NH2, —NH—NH2, —NH—OH, —NHR3, —NR3R4, —OH, or —OR3, in which R3 and R4 are any of C1-10 alkyl, C2-10 alkenyl, C2-10 alkinyl, C7-16 phenylalkyl, —C6H5, or —CH(C6H5)2;
provided that if A29 is Agm then A30 and R2 are absent, and if A30 is Agm then R2 is absent, and pharmaceutically acceptable salts thereof.

24 more elements