CA2226177A1 - Analogs of parathyroid hormone - Google Patents
Analogs of parathyroid hormoneInfo
- Publication number
- CA2226177A1 CA2226177A1 CA002226177A CA2226177A CA2226177A1 CA 2226177 A1 CA2226177 A1 CA 2226177A1 CA 002226177 A CA002226177 A CA 002226177A CA 2226177 A CA2226177 A CA 2226177A CA 2226177 A1 CA2226177 A1 CA 2226177A1
- Authority
- CA
- Canada
- Prior art keywords
- cha
- aib
- leu
- phe
- peptide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 108090000445 Parathyroid hormone Proteins 0.000 title claims abstract 3
- 102000003982 Parathyroid hormone Human genes 0.000 title claims abstract 3
- 239000000199 parathyroid hormone Substances 0.000 title claims abstract 3
- 229960001319 parathyroid hormone Drugs 0.000 title abstract 2
- 108090000765 processed proteins & peptides Proteins 0.000 claims abstract 38
- 150000003839 salts Chemical class 0.000 claims 31
- 108010067557 parathyroid hormone (1-34)amide Proteins 0.000 claims 29
- RRBCHMCWWOHRQL-UMXFMPSGSA-N parathyroid hormone (1-34)amide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)C1=CN=CN1 RRBCHMCWWOHRQL-UMXFMPSGSA-N 0.000 claims 29
- 229910052736 halogen Inorganic materials 0.000 claims 10
- 150000002367 halogens Chemical class 0.000 claims 10
- 125000005020 hydroxyalkenyl group Chemical group 0.000 claims 8
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims 8
- 125000003884 phenylalkyl group Chemical group 0.000 claims 8
- ODKSFYDXXFIFQN-UHFFFAOYSA-N Arginine Chemical compound OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims 7
- 125000004400 (C1-C12) alkyl group Chemical group 0.000 claims 6
- 125000003342 alkenyl group Chemical group 0.000 claims 6
- 125000004642 (C1-C12) alkoxy group Chemical group 0.000 claims 4
- 101000909637 Homo sapiens Transcription factor COE1 Proteins 0.000 claims 4
- 102100024207 Transcription factor COE1 Human genes 0.000 claims 4
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 4
- 125000001183 hydrocarbyl group Chemical group 0.000 claims 4
- 125000000217 alkyl group Chemical group 0.000 claims 2
- 101000731000 Homo sapiens Membrane-associated progesterone receptor component 1 Proteins 0.000 claims 1
- 102100032399 Membrane-associated progesterone receptor component 1 Human genes 0.000 claims 1
- 101150100052 NCOA6 gene Proteins 0.000 claims 1
- OGBMKVWORPGQRR-UMXFMPSGSA-N teriparatide Chemical compound C([C@H](NC(=O)[C@H](CCSC)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@@H](N)CO)C(C)C)[C@@H](C)CC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1N=CNC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(O)=O)C1=CNC=N1 OGBMKVWORPGQRR-UMXFMPSGSA-N 0.000 claims 1
- 125000000539 amino acid group Chemical group 0.000 abstract 5
- BVAUMRCGVHUWOZ-ZETCQYMHSA-N (2s)-2-(cyclohexylazaniumyl)propanoate Chemical compound OC(=O)[C@H](C)NC1CCCCC1 BVAUMRCGVHUWOZ-ZETCQYMHSA-N 0.000 abstract 1
- FUOOLUPWFVMBKG-UHFFFAOYSA-N 2-Aminoisobutyric acid Chemical compound CC(C)(N)C(O)=O FUOOLUPWFVMBKG-UHFFFAOYSA-N 0.000 abstract 1
- PECYZEOJVXMISF-UHFFFAOYSA-N 3-aminoalanine Chemical compound [NH3+]CC(N)C([O-])=O PECYZEOJVXMISF-UHFFFAOYSA-N 0.000 abstract 1
- QUOGESRFPZDMMT-UHFFFAOYSA-N L-Homoarginine Natural products OC(=O)C(N)CCCCNC(N)=N QUOGESRFPZDMMT-UHFFFAOYSA-N 0.000 abstract 1
- QUOGESRFPZDMMT-YFKPBYRVSA-N L-homoarginine Chemical compound OC(=O)[C@@H](N)CCCCNC(N)=N QUOGESRFPZDMMT-YFKPBYRVSA-N 0.000 abstract 1
- LRQKBLKVPFOOQJ-YFKPBYRVSA-N L-norleucine Chemical compound CCCC[C@H]([NH3+])C([O-])=O LRQKBLKVPFOOQJ-YFKPBYRVSA-N 0.000 abstract 1
- 239000012634 fragment Substances 0.000 abstract 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/635—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Biochemistry (AREA)
- Zoology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Peptide variants of fragment (1-34) of parathyroid hormone, in which at least one of the amino acid residues at positions 7, 11, 23, 24, 27, 28 and 31 is cyclohexylalanine, or at least one of the amino acid residues at positions 3, 16, 17, 18, 19 and 34 is .alpha.-aminoisobutyric acid; or, alternatively, at least the amino acid residue at position 1 is .alpha.,.beta.-diaminopropionic acid, the amino acid residue at position 27 is homoarginine, or the amino acid residue at position 31 is norleucine.
Claims (31)
1. A peptide of the formula:
wherein A1 is Ser, Ala, or Dap;
A3 is Ser, Thr, or Aib;
A5 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH3;
A7 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
A11 is Leu, Nle, Ile, Cha, ,.beta.-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH3;
A12 is Gly or Aib;
A15 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A16 is Ser, Asn, Ala, or Aib;
A17 is Ser, Thr, or Aib;
A18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;
A19 is Glu or Aib;
A21 is Val, Cha, or Met;
A23 is Trp or Cha;
A24 is Leu or Cha;
A27 is Lys, Aib, Leu, hArg, Gln, or Cha;
A28 is Leu or Cha;
A30 is Asp or Lys;
A31 is Val, Nle, Cha, or deleted;
A32 is His or deleted;
A33 is Asn or deleted;
A34 is Phe, Tyr, Amp, Aib, or deleted;
each of R1 and R2 is, independently, H, C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxy-phenylalkyl, or C11-20 hydroxynapthylalkyl; and R3 is OH, NH2, C1-12 alkoxy, or NH-Y-CH2-Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H, or CONH2;
provided that at least one of A5, A7, A8, A11, A15, A18, A21, A23, A24, A27, A28, and A31 is Cha, or at least one of A3, A12, A16, A17, A18, A19, and A34 is Aib; or a pharmaceutically acceptable salt thereof.
wherein A1 is Ser, Ala, or Dap;
A3 is Ser, Thr, or Aib;
A5 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH3;
A7 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
A11 is Leu, Nle, Ile, Cha, ,.beta.-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH3;
A12 is Gly or Aib;
A15 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A16 is Ser, Asn, Ala, or Aib;
A17 is Ser, Thr, or Aib;
A18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;
A19 is Glu or Aib;
A21 is Val, Cha, or Met;
A23 is Trp or Cha;
A24 is Leu or Cha;
A27 is Lys, Aib, Leu, hArg, Gln, or Cha;
A28 is Leu or Cha;
A30 is Asp or Lys;
A31 is Val, Nle, Cha, or deleted;
A32 is His or deleted;
A33 is Asn or deleted;
A34 is Phe, Tyr, Amp, Aib, or deleted;
each of R1 and R2 is, independently, H, C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxy-phenylalkyl, or C11-20 hydroxynapthylalkyl; and R3 is OH, NH2, C1-12 alkoxy, or NH-Y-CH2-Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H, or CONH2;
provided that at least one of A5, A7, A8, A11, A15, A18, A21, A23, A24, A27, A28, and A31 is Cha, or at least one of A3, A12, A16, A17, A18, A19, and A34 is Aib; or a pharmaceutically acceptable salt thereof.
2. A peptide of claim 1, wherein at least one of A7, A11, A15, A23, A24, A27, A28, and A31 is Cha; or a pharmaceutically acceptable salt thereof.
3. A peptide of claim 2, wherein A3 is Ser;
A5 is Ile;
A7 is Leu or Cha;
A8 is Met, Nva, Leu, Val, Ile, or Nle;
A11 is Leu or Cha;
A12 is Gly;
A15 is Leu or Cha;
A16 is Asn or Aib;
A17 is Ser;
A18 is Met or Nle;
A21 is Val;
A27 is Lys, hArg, or Cha;
A32 is His;
A31 is Val, Nle, or Cha;
A33 is Asn;
A34 is Phe, Tyr, Amp, or Aib;
R1 is H;
R2 is H; and R3 is NH2;
or a pharmaceutically acceptable salt thereof.
A5 is Ile;
A7 is Leu or Cha;
A8 is Met, Nva, Leu, Val, Ile, or Nle;
A11 is Leu or Cha;
A12 is Gly;
A15 is Leu or Cha;
A16 is Asn or Aib;
A17 is Ser;
A18 is Met or Nle;
A21 is Val;
A27 is Lys, hArg, or Cha;
A32 is His;
A31 is Val, Nle, or Cha;
A33 is Asn;
A34 is Phe, Tyr, Amp, or Aib;
R1 is H;
R2 is H; and R3 is NH2;
or a pharmaceutically acceptable salt thereof.
4. A peptide of claim 3, wherein at least one of A7 and A11 is Cha; or a pharmaceutically acceptable salt thereof.
5. A peptide of claim 4, wherein said peptide is [Cha7, 11]hPTH(1-34)NH2, [Cha7, 11, Nle8, 18, Tyr34]hPTH(1-34)NH2; [Cha11]hPTH(1-34)NH2; [Cha7,11,15]hPTH(1-34)NH2; or [Cha7]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
6. A peptide of claim 3, wherein at least one of A15, A23, A24, A27, A28, and A31 is Cha; or a pharmaceutically acceptable salt thereof.
7. A peptide of claim 6, wherein said peptide is [Cha23]hPTH(1-34)NH2, [Cha24]hPTH(1-34)NH2, [Nle8, 18, Cha27]hPTH (1-34)NH2, [Cha23]hPTH(1-34)NH2, [Cha31]hPTH(1-34 NH2, [Cha24, 28, 31]hPTH(1-34)NH2; [Cha24, 28, 31, Lys30]hPTH(1-34)NH2; [Cha28, 31]hPTH(1-34)NH2; or [Cha15]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
8. A peptide of claim 1, wherein at least one of A3, A12, A16, A17, A18, A19, and A34 is Aib; or a pharmaceutically acceptable salt thereof.
9. A peptide of claim 8, wherein A3 is Ser or Aib;
A5 is Ile;
A7 is Leu or Cha;
A8 is Met, Nva, Leu, Val, Ile, or Nle;
A11 is Leu or Cha;
A15 is Leu or Cha;
A16 is Asn or Aib;
A18 is Met, Aib, or Nle;
A21 is Val;
A27 is Lys, Aib, Leu, hArg, or Cha;
A31 is Val, Nle, or Cha;
A32 is His;
A33 is Asn;
A34 is Phe, Tyr, Amp, or Aib;
R1 is H;
R2 is H; and R3 is NH2;
or a pharmaceutically acceptable salt thereof.
A5 is Ile;
A7 is Leu or Cha;
A8 is Met, Nva, Leu, Val, Ile, or Nle;
A11 is Leu or Cha;
A15 is Leu or Cha;
A16 is Asn or Aib;
A18 is Met, Aib, or Nle;
A21 is Val;
A27 is Lys, Aib, Leu, hArg, or Cha;
A31 is Val, Nle, or Cha;
A32 is His;
A33 is Asn;
A34 is Phe, Tyr, Amp, or Aib;
R1 is H;
R2 is H; and R3 is NH2;
or a pharmaceutically acceptable salt thereof.
10. A peptide of claim 9, wherein at least one of A3, A12, A16, A17, A19, and A34 is Aib; or a pharmaceutically acceptable salt thereof.
11. A peptide of claim 10, wherein said peptide is [Aib16]hPTH(1-34)NH2, [Aib19]hPTH(1-34)NH2, [Aib34]hPTH(1-34)NH2; [Aib16, 19]hPTH(1-34)NH2;
[Aib3]hPTH(1-34)NH2; [Aib17]hPTH(1-34)NH2; or [Aib12]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
[Aib3]hPTH(1-34)NH2; [Aib17]hPTH(1-34)NH2; or [Aib12]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
12. A peptide of claim 1 wherein at least one of A7, A11, A15, A23, A24, A27, A28, and A31 is Cha and at east one of A3, A12, A16. A17, A18, A19, and A34 is Aib;
or a pharmaceutically acceptable salt thereof.
or a pharmaceutically acceptable salt thereof.
13. A peptide of claim 12, wherein A3 is Ser or Aib;
A5 is Ile;
A7 is Leu or Cha;
A8 is Met, Nva, Leu, Val, Ile, or Nle;
A11 is Leu or Cha;
A15 is Leu or Cha;
A16 is Asn or Aib;
A18 is Met, Aib, or Nle;
A21 is Val;
A27 is Lys, Aib, Leu, hArg, or Cha;
A31 is Val, Nle, or Cha;
A32 is His;
A33 is Asn;
A34 is Phe, Tye, Amp, or Aib;
R1 is H;
R2 is H; and R3 is NH2;
or a pharmaceutically acceptable salt thereof.
A5 is Ile;
A7 is Leu or Cha;
A8 is Met, Nva, Leu, Val, Ile, or Nle;
A11 is Leu or Cha;
A15 is Leu or Cha;
A16 is Asn or Aib;
A18 is Met, Aib, or Nle;
A21 is Val;
A27 is Lys, Aib, Leu, hArg, or Cha;
A31 is Val, Nle, or Cha;
A32 is His;
A33 is Asn;
A34 is Phe, Tye, Amp, or Aib;
R1 is H;
R2 is H; and R3 is NH2;
or a pharmaceutically acceptable salt thereof.
14. A peptide of claim 13, wherein at least one of A7 and A11 is Cha and at least one of A16, A19, and A34 is Aib; or a pharmaceutically acceptable salt thereof.
15. A peptide of claim 14, wherein said peptide is [Cha7, 11 Nle8, 18, Aib 16, 19, Tyr34]hPTH(1-34)NH2, [Cha7, 11, Nle8, 18, 31, Aib16, 19, Tyr34]hPTH(1-34)NH2;
[Cha7, 11, Aib19]hPTH(1-34)NH2; [Cha7, 11, Aib16]hPTH(1-34)NH ;
[Cha7, 11, Nle8, 18, Aib34]hPTH(1-34)NH2; or [Cha7, 11, Aib19, Lys30]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
[Cha7, 11, Aib19]hPTH(1-34)NH2; [Cha7, 11, Aib16]hPTH(1-34)NH ;
[Cha7, 11, Nle8, 18, Aib34]hPTH(1-34)NH2; or [Cha7, 11, Aib19, Lys30]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
16. A peptide of claim 13, wherein at least one of A24, A28, and A31 is Cha and at least one of A16 and A17 is Aib; or a pharmaceutically acceptable salt thereof.
17. A peptide of claim 16, wherein said peptide is [Cha28 Nle8, 18, Aib16, 19, Tyr34]hPTH(1-34)NH2, or [Cha28, Aib16,19] PTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
18. A peptide of the formula:
wherein A3 is Ser, Thr, or Aib;
A5 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH3;
A7 is Leu, Ile, Nle, Cha, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is H, OH, a halogen, or CH3;
A8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
A11 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH3;
A12 is Gly or Aib;
A15 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A16 is Ser, Asn, Ala, or Aib;
A17 is Ser, Thr, or Aib;
A18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;
A19 is Glu or Aib;
A21 is Val, Cha, or Met;
A23 is Trp or Cha;
A24 is Leu or Cha;
A27 is Lys, Aib, Leu, hArg, Gln, or Cha;
A28 is Leu or Cha;
A30 is Asp or Lys;
A31 is Val, Nle, Cha, or deleted;
A32 is His or deleted;
A33 is Asn or deleted;
A34 is Phe, Tyr, Amp, Aib, or deleted;
each of R1 and R2 is, independently, H, C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxy-phenylalkyl, or C11-20 hydroxynapthylalkyl;
R3 is OH, NH2, C1-12 alkoxy, or NH-Y-CH2-Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H, or CONH2;
provided that at least A1 is Dap, A7 is .beta.-Nal, Trp, Pal, Phe, or p-X-Phe; A15 is .beta.-Nal, Trp, Pal, Phe, or p-X-Phe, A27 is hArg, or A31 is Nle; or a pharmaceutically acceptable salt thereof.
wherein A3 is Ser, Thr, or Aib;
A5 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe or p-X-Phe, in which X is OH, a halogen, or CH3;
A7 is Leu, Ile, Nle, Cha, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is H, OH, a halogen, or CH3;
A8 is Met, Nva, Leu, Val, Ile, Cha, or Nle;
A11 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe or p-X-Phe in which X is OH, a halogen, or CH3;
A12 is Gly or Aib;
A15 is Leu, Nle, Ile, Cha, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A16 is Ser, Asn, Ala, or Aib;
A17 is Ser, Thr, or Aib;
A18 is Met, Nva, Leu, Val, Ile, Nle, Cha, or Aib;
A19 is Glu or Aib;
A21 is Val, Cha, or Met;
A23 is Trp or Cha;
A24 is Leu or Cha;
A27 is Lys, Aib, Leu, hArg, Gln, or Cha;
A28 is Leu or Cha;
A30 is Asp or Lys;
A31 is Val, Nle, Cha, or deleted;
A32 is His or deleted;
A33 is Asn or deleted;
A34 is Phe, Tyr, Amp, Aib, or deleted;
each of R1 and R2 is, independently, H, C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxy-phenylalkyl, or C11-20 hydroxynapthylalkyl;
R3 is OH, NH2, C1-12 alkoxy, or NH-Y-CH2-Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H, or CONH2;
provided that at least A1 is Dap, A7 is .beta.-Nal, Trp, Pal, Phe, or p-X-Phe; A15 is .beta.-Nal, Trp, Pal, Phe, or p-X-Phe, A27 is hArg, or A31 is Nle; or a pharmaceutically acceptable salt thereof.
19. A peptide of claim 18, wherein A1 is Ser, Gly, or Dap;
A3 is Ser or Aib;
A8 is Met, Nva, Leu, Val, Ile, or Nle;
A16 is Asn or Aib;
A18 is Met, Aib, or Nle;
A21 is Val;
A27 is Lys, Aib, Leu, hArg, or Cha;
A31 is Val, Nle, or Cha;
A32 is His;
A33 is Asn;
A34 is Phe, Tyr, Amp, or Aib;
R1 is H;
R2 is H; and R3 is NH2;
or a pharmaceutically acceptable salt thereof.
A3 is Ser or Aib;
A8 is Met, Nva, Leu, Val, Ile, or Nle;
A16 is Asn or Aib;
A18 is Met, Aib, or Nle;
A21 is Val;
A27 is Lys, Aib, Leu, hArg, or Cha;
A31 is Val, Nle, or Cha;
A32 is His;
A33 is Asn;
A34 is Phe, Tyr, Amp, or Aib;
R1 is H;
R2 is H; and R3 is NH2;
or a pharmaceutically acceptable salt thereof.
20. A peptide of claim 19, wherein said peptide is [Nle31]hPTH(1-34)NH2, [hArg27 ]hPTH(1-34)NH2, or [Dap1, Nle8, 18, Tyr34]hPTH(1-34)NH2; or a pharmaceutically acceptable salt thereof.
21. A peptide of the formula:
wherein A1 is Ala, Ser, or Dap;
A3 is Ser or Aib;
A5 is His, Ile, or Cha;
A7 is Leu, Cha, Nle, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A8 is Leu, Met, or Cha;
A10 is Asp or Asn;
A11 is Lys, Leu, Cha, Phe, or .beta.-Nal;
A12 is Gly or Aib;
A14 is Ser or His;
A15 is Ile, or Cha;
A16 is Gln or Aib;
A17 is Asp or Aib;
A18 is Leu, Aib, or Cha;
A19 is Arg or Aib;
A22 is Phe, Glu, Aib, or Cha;
A23 is Phe, Leu, Lys, or Cha;
A24 is Leu, Lys, or Cha;
A25 is His, Aib, or Glu;
A26 is His, Aib, or Lys;
A27 is Leu, Lys, or Cha;
A28 is Ile, Leu, Lys, or Cha;
A29 is Ala, Glu, or Aib;
A30 is Glu, Cha, Aib, or Lys;
A31 is Ile, Leu, Cha, Lys, or deleted;
A32 is His or deleted;
A33 is Thr or deleted;
A34 is Ala or deleted;
each of R1 and R2 is, independently, H, C1-12 alkanyl, C7-20 phenylalkyl, C11-20 napthyalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; and R3 is OH, NH2, C1-12 alkoxy, or NH-Y-CH2-Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
provided that at least one of A5, A7, A8, A11, A15, A18, A22, A23, A24, A27, A28, A30, or A31 is Cha, or at least one of A3, A12, A16, A17, A18, A19, A22. A25, A26, A29, A30, or A34 is Aib; or a pharmaceutically acceptable salt thereof.
wherein A1 is Ala, Ser, or Dap;
A3 is Ser or Aib;
A5 is His, Ile, or Cha;
A7 is Leu, Cha, Nle, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A8 is Leu, Met, or Cha;
A10 is Asp or Asn;
A11 is Lys, Leu, Cha, Phe, or .beta.-Nal;
A12 is Gly or Aib;
A14 is Ser or His;
A15 is Ile, or Cha;
A16 is Gln or Aib;
A17 is Asp or Aib;
A18 is Leu, Aib, or Cha;
A19 is Arg or Aib;
A22 is Phe, Glu, Aib, or Cha;
A23 is Phe, Leu, Lys, or Cha;
A24 is Leu, Lys, or Cha;
A25 is His, Aib, or Glu;
A26 is His, Aib, or Lys;
A27 is Leu, Lys, or Cha;
A28 is Ile, Leu, Lys, or Cha;
A29 is Ala, Glu, or Aib;
A30 is Glu, Cha, Aib, or Lys;
A31 is Ile, Leu, Cha, Lys, or deleted;
A32 is His or deleted;
A33 is Thr or deleted;
A34 is Ala or deleted;
each of R1 and R2 is, independently, H, C1-12 alkanyl, C7-20 phenylalkyl, C11-20 napthyalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2-12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; and R3 is OH, NH2, C1-12 alkoxy, or NH-Y-CH2-Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
provided that at least one of A5, A7, A8, A11, A15, A18, A22, A23, A24, A27, A28, A30, or A31 is Cha, or at least one of A3, A12, A16, A17, A18, A19, A22. A25, A26, A29, A30, or A34 is Aib; or a pharmaceutically acceptable salt thereof.
22. A peptide of claim 21, wherein at A22 is Phe or Cha; A23 is Phe or Cha; A25 is His; A26 is His; A27 is Leu or Cha; A28 is Ile or Cha; A29 is Ala; A30 is Glu or Lys; A31 is Ile or Cha; A32 is His; A33 is Thr; and A34 is Ala; or a pharmaceutically acceptable salt thereof.
23. A peptide of claim 22, wherein at least one of A7 and A11 is Cha; or a pharmaceutically acceptable salt thereof.
24. A peptide of claim 22, wherein at least one of A16 or A19 is Aib; or a pharmaceutically acceptable salt thereof.
25. A peptide of claim 21, wherein A22 is Glu, Aib, or Cha; A23 is Leu, Lys, or Cha; A25 is Aib or Glu;
A26 is Aib or Lys; A28 is Leu, Lys, or Cha; A29 is Glu or Aib; A30 is Cha, Aib, or Lys; A31 is Leu, Cha, or Lys; A32 is His; A33 is Thr; and A34 is Ala; or a pharmaceutically acceptable salt thereof.
A26 is Aib or Lys; A28 is Leu, Lys, or Cha; A29 is Glu or Aib; A30 is Cha, Aib, or Lys; A31 is Leu, Cha, or Lys; A32 is His; A33 is Thr; and A34 is Ala; or a pharmaceutically acceptable salt thereof.
26. A peptide of claim 25, wherein at least one of A7 and All is Cha; or a pharmaceutically acceptable salt thereof.
27. A peptide of claim 25, wherein at least one of A16 or A19 is Aib; or a pharmaceutically acceptable salt thereof.
28. A peptide of the formula:
wherein A1 is Ala, Ser, or Dap;
A3 is Ser or Aib;
A5 is His, Ile, or Cha;
A7 is Leu, Cha, Nle, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A8 is Leu, Met, or Cha;
A10 is Asp or Asn;
A11 is Lys, Leu, Cha, Phe, or .beta.-Nal;
A12 is Gly or Aib;
A14 is Ser or His;
A15 is Ile, or Cha;
A16 is Gln or Aib;
A17 is Asp or Aib;
A18 is Leu, Aib, or Cha;
A19 is Arg or Aib;
A22 is Phe, Glu, Aib, or Cha;
A23 is Phe, Leu, Lys, or Cha;
A24 is Leu, Lys, or Cha;
A25 is His, Aib, or Glu;
A26 is His, Aib, or Lys;
A27 is Leu, Lys, or Cha;
A28 is Ile, Leu, Lys, or Cha;
A29 is Ala, Glu, or Aib;
A30 is Glu, Cha, Aib, or Lys;
A31 is Ile, Leu, Cha, Lys, or deleted;
A32 is His or deleted;
A33 is Thr or deleted;
A34 is Ala or deleted;
each of R1 and R2 is, independently, H, C1-12 alkanyl, C7-20 phenylalkyl, C11-20 napthyalkyl, C1-12, hydroxyalkyl, C2- 12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2 12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; and R3 is OH, NH2, C1-12 alkoxy, or NH-Y-CH2-Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
provided that at least one of A23, A24, A27, A28, or A31 is Lys; or a pharmaceutically acceptable salt thereof.
wherein A1 is Ala, Ser, or Dap;
A3 is Ser or Aib;
A5 is His, Ile, or Cha;
A7 is Leu, Cha, Nle, .beta.-Nal, Trp, Pal, Phe, or p-X-Phe in which X is OH, a halogen, or CH3;
A8 is Leu, Met, or Cha;
A10 is Asp or Asn;
A11 is Lys, Leu, Cha, Phe, or .beta.-Nal;
A12 is Gly or Aib;
A14 is Ser or His;
A15 is Ile, or Cha;
A16 is Gln or Aib;
A17 is Asp or Aib;
A18 is Leu, Aib, or Cha;
A19 is Arg or Aib;
A22 is Phe, Glu, Aib, or Cha;
A23 is Phe, Leu, Lys, or Cha;
A24 is Leu, Lys, or Cha;
A25 is His, Aib, or Glu;
A26 is His, Aib, or Lys;
A27 is Leu, Lys, or Cha;
A28 is Ile, Leu, Lys, or Cha;
A29 is Ala, Glu, or Aib;
A30 is Glu, Cha, Aib, or Lys;
A31 is Ile, Leu, Cha, Lys, or deleted;
A32 is His or deleted;
A33 is Thr or deleted;
A34 is Ala or deleted;
each of R1 and R2 is, independently, H, C1-12 alkanyl, C7-20 phenylalkyl, C11-20 napthyalkyl, C1-12, hydroxyalkyl, C2- 12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; or one and only one of R1 and R2 is COE1 in which E1 is C1-12 alkyl, C2 12 alkyl, C2-12 alkenyl, C7-20 phenylalkyl, C11-20 napthylalkyl, C1-12 hydroxyalkyl, C2-12 hydroxyalkenyl, C7-20 hydroxyphenylalkyl, or C11-20 hydroxynapthylalkyl; and R3 is OH, NH2, C1-12 alkoxy, or NH-Y-CH2-Z in which Y is a C1-12 hydrocarbon moiety and Z is H, OH, CO2H or CONH2;
provided that at least one of A23, A24, A27, A28, or A31 is Lys; or a pharmaceutically acceptable salt thereof.
29. A peptide of claim 28, wherein A22 is Glu, Aib, or Cha; A23 is Leu, Lys, or Cha; A25 is Aib or Glu;
A26 is Aib or Lys; A28 is Leu, Lys, or Cha; A29 is Glu or Aib; A30 is Cha, Aib, or Lys; A31 is Leu, Cha, or Lys; A32 is His; A33 is Thr; and A34 is Ala; or a pharmaceutically acceptable salt thereof.
A26 is Aib or Lys; A28 is Leu, Lys, or Cha; A29 is Glu or Aib; A30 is Cha, Aib, or Lys; A31 is Leu, Cha, or Lys; A32 is His; A33 is Thr; and A34 is Ala; or a pharmaceutically acceptable salt thereof.
30. A peptide of claim 29, wherein at least one of A7 and A11 is Cha; or a pharmaceutically acceptable salt thereof.
31. A peptide of claim 29, wherein at least one of A16 or A19 is Aib; or a pharmaceutically acceptable salt thereof.
Applications Claiming Priority (7)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US110595P | 1995-07-13 | 1995-07-13 | |
| US60/001,105 | 1995-07-13 | ||
| US330595P | 1995-09-06 | 1995-09-06 | |
| US60/003,305 | 1995-09-06 | ||
| US08/626,186 US5723577A (en) | 1995-07-13 | 1996-03-29 | Analogs of parathyroid hormone |
| US08/626,186 | 1996-03-29 | ||
| PCT/US1996/011292 WO1997002834A1 (en) | 1995-07-13 | 1996-07-03 | Analogs of parathyroid hormone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2226177A1 true CA2226177A1 (en) | 1997-01-30 |
| CA2226177C CA2226177C (en) | 2010-09-07 |
Family
ID=42727572
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2226177A Expired - Lifetime CA2226177C (en) | 1995-07-13 | 1996-07-03 | Analogs of parathyroid hormone |
Country Status (1)
| Country | Link |
|---|---|
| CA (1) | CA2226177C (en) |
-
1996
- 1996-07-03 CA CA2226177A patent/CA2226177C/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| CA2226177C (en) | 2010-09-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AR011517A1 (en) | PROTEIN ANALOGS RELATED TO PARATHYROID HORMONE | |
| Schwabe et al. | Primary structure of the B-chain of porcine relaxin | |
| USRE40850E1 (en) | Analogs of parathyroid hormone | |
| US7410948B2 (en) | Analogs of parathyroid hormone | |
| EP1405861B1 (en) | Analogs of parathyroid hormone | |
| AR019131A1 (en) | ANALOGS OF PITUITARY POLYPEPTIDES THAT ACTIVATE CYCLASS ADENYLATE, A PHARMACEUTICAL COMPOSITION THAT INCLUDES THEM, AND THE USE OF SUCH PEPTIDES FOR LAMANUFACTURE OF A MEDICINAL PRODUCT | |
| AU1918300A (en) | Amino-terminal modified parathyroid hormone (pth) analogs | |
| ATE178908T1 (en) | LYS(B28) INSULINE. ANALOGUES OF HUMAN INSULIN | |
| Zarandi et al. | Synthesis and in vitro evaluation of new potent antagonists of growth hormone-releasing hormone (GH-RH) | |
| CA2350914A1 (en) | Treatment of tumors by administration of growth hormone releasing compounds and their antagonists | |
| CA2226177A1 (en) | Analogs of parathyroid hormone | |
| Chang et al. | Purification, characterization, and molecular cloning of gonadotropin subunits of silver carp (Hypophthalmichthys molitrix) | |
| JPH09157294A (en) | Parathyroid hormone derivative | |
| Yanaihara et al. | Alternative approach for human proinsulin synthesis | |
| MXPA99006387A (en) | Analogs of parathyroid hormone |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| EEER | Examination request | ||
| MKEX | Expiry |
Effective date: 20160704 |