US2004063631A1PendingUtilityA1
Compounds with the biological activity of vasoactive intestinal peptide for the treatment of pulmonary and arteriolar hypertension
Priority: Nov 28, 2000Filed: Nov 22, 2001Published: Apr 1, 2004
Est. expiryNov 28, 2020(expired)· nominal 20-yr term from priority
Inventors:Lutz-Henning Block
A61P 9/04A61P 9/00A61P 35/00A61P 9/12A61K 38/00C07K 14/57563A61P 11/00
22
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Claims
Abstract
The present invention relates to peptides which are highly biologically and pharmacologically active as therapeutic drug for the treatment of diseases related to hypertension, especially in medical interventions involving dilatation and remodelling of arterial blood vessels, either in the pulmonary or in the systemic circulation. The peptides which can be used according to the invention for the treatment of said diseases comprises at least one specific highly conservative amino acid residue sequence which seem to play an important role in connection with pulmonary and arteriolar hypertension events. It could be shown that the known naturally occurring peptides “vasoactive intestinal peptide (VIP)” and pituitary adenylate cyclaseactivating polypeptide (PACAP)”, having these specific sequences are potent drugs which can be successfully used for treatment of primary pulmonary hypertension (PPH), secondary pulmonary hypertension (SPH), and hypertension of the systemic circulation. Furthermore, the present invention discloses pharmaceutical compositions useful for treatment of PPH, SPH, and hypertension of the systemic circulation within said methods.
Claims
exact text as granted — not AI-modified1 . A use of a compound for the manufacture of a medicament for the treatment of a patient suffering from a disease or a disorder correlated directly or indirectly with hypertension symptoms in human lung and/or heart tissue, wherein said compound is a peptide or a polypeptide comprising the following amino acid sequence:
Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu.
2 . A use according to claim 1 , wherein said peptide or a polypeptide further comprises at least one of the following amino acid sequences:
His-Ser-Asp; Phe-Thr-Asp.
3 . A use according to claim 1 , wherein said peptide or a polypeptide further comprises the amino acid sequences His-Ser-Asp and Phe-Thr-Asp.
4 . A use according to claim 1 , wherein said peptide or a polypeptide has the following amino acid sequence:
(A) n -Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-(B) m wherein A, B is any natural occurring amino acid residue, A and B are independently from each other; and n, m is an integer having values from 0-25; n and m being independently from each other.
5 . A use according to claim 4 , wherein, if n>2, (A) n has the following sequence:
(X) o -Phe-Thr-Asp-(Y) p wherein X, Y is any natural occurring amino acid residue, X and Y are independently from each other; and o, p is an integer having values from 0-11, o and p being independently from each other.
6 . A use according to claim 5 , wherein, if o>2 (X) 0 has the following sequence:
(X′) q -His-Ser-Asp-(X″) r wherein X′, X″ is any natural occurring amino acid residue, X′ and X″ are independently from each other; and r, q is an integer having values from 0-4, r and q being independently from each other.
7 . A use according to claim 4 , wherein the sequence of said peptide or polypeptide is selected from the following group:
(i)
Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu;
(ii)
Phe-Thr-Asp-X 1 -X 2 -X 3 -X 4 -X 5 -Arg-Lys-Gln-Met-
Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn
(iii)
Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-
Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-
Asn;
(iv)
Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-
Met-Ala-Val-Lys-Lys-Tyr-Leu;
(v)
His-Ser-Asp-X 1 -X 2 -Phe-Thr-Asp-X 3 -X 4 -X 5 -X 6 -
X 7 -Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu;
(vi)
His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-
Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-
Leu,
(vi)
His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-
Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-
Leu;
(vii)
His-Ser-Asp-X 1 -X 2 -Phe-Thr-Asp-X 3 -X 4 -X 5 -X 6 -
X 7 -Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-
X 8 -X 9 -X 10 -X 11 (-X 12 );
(viii)
His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-
Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-
Leu-Asn-Ser-Ile-Leu-Asn (VIP);
(ix)
His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-
Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-
Leu-Ala-Ala-Val-Leu (PACAP-27);
(x)
His-Ser-Asp-X 1 -X 2 -Phe-Thr-Asp-X 3 -X 4 -X 5 -X 6 -
X 7 -Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-
X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -
X 19 -X 20 -X 21 -X 22 ;
(xi)
His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-
Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-
Leu-Ala-Ala-Val-Leu-Gly-Lys-Arg-Tyr-Lys-Gln-
Arg-Val-Lys-Asn-Lys (PACAP-38);
wherein X 1 -X 22 is any naturally occurring amino acid residue.
8 . A use according to any of the claims 1 - 7 , wherein any of said peptides or polypeptides is an analogue or derivative having the same biological function.
9 . A use according to claim 8 , wherein any of said peptides or polypeptides is an a stabilized form.
10 . A use according to any of the claims 1 - 9 , wherein said disease or disorder is caused by an increased vessel tone of human pulmonary arterial rings.
11 . A use according to any of the claims 1 - 9 , wherein said disease or disorder is caused by an increased intracellular free calcium concentration in human vascular smooth muscle cells (VSMC).
12 . A use according to any of the claims 1 - 9 , wherein said disease or disorder is caused by an increased proliferation of human vascular smooth muscle cells (VSMC) of human pulmonary arterial vessels.
13 . A use according to any of the claims 1 - 12 , wherein said disease is primary pulmonary hypertension (PPH).
14 . A use according to any of the claims 1 - 12 , wherein said disease is chronic obstructive pulmonary disease (COPD).
15 . A use according to claim 14 , wherein said is chronic obstructive pulmonary disease is secondary pulmonary hypertension (SPH).
16 . A use according any of the claims 1 - 9 , wherein said disease is arteriolar hypertension.
17 . A use according to claim 16 , wherein said arteriolar hypertension is associated with PPH.
18 . A use according to any of the claim 1 - 9 , wherein said disease is heart failure associated with PPH.
19 . A use according to claim 13 , wherein the pulmonary arterial pressure is reduced to more than 20% after administration of any of said peptides or polypeptides.
20 . A use according to claim 16 or 17 , wherein the diastolic pressure is reduced to 5-25% and the systolic blood pressure is reduced to 10-30% after administration of any of said peptides or polypeptides.
21 . A use according to claim 1 wherein said peptide or polypeptide has the biological function of, or is functionally similar to VIP or PACAP, or any biologically active derivative, truncated form, analogue or fusion protein thereof.
22 . A peptide or a polypeptide having the following sequence
(A) n - Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-(B) m wherein A, B is any natural occurring amino acid residue, A and B are independently from each other; and n, m is an integer having values from 0-25, n and m are independently from each other, provided that VIP, PACAP and PACAP-27 (truncated PACAP) is excluded.
23 . A peptide or a polypeptide according to claim 22 , wherein, if n>2, (A) n has the following sequence:
(X) o -Phe-Thr-Asp-(Y) p wherein X, Y is any natural occurring amino acid residue, X and Y are independently from each other; and o, p is an integer having values from 0-11, o and p are independently from each other.
24 . A peptide or a polypeptide according to claim 23 , wherein, if o>2 (X) o has the following sequence:
(X′) q -His-Ser-Asp- (X″) r wherein X′, X″ is any natural occurring amino acid residue, X′ and X″ are independently from each other; and r, q is an integer having values from 0-4, r and q are independently from each other.
25 . A peptide or a polypeptide according to claim 22 , wherein the sequence of said peptide or polypeptide is selected from the following group:
(i)
Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu;
(ii)
Phe-Thr-Asp-X 1 -X 2 -X 3 -X 4 -X 5 -Arg-Lys-Gln-Met-
Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn
(iii)
Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-
Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-
Asn;
(iv)
Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-
Met-Ala-Val-Lys-Lys-Tyr-Leu;
(v)
His-Ser-Asp-X 1 -X 2 -Phe-Thr-Asp-X 3 -X 4 -X 5 -X 6 -
X 7 -Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu;
(vi)
His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-
Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-
Leu,
(vi)
His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-
Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-
Leu;
(vii)
His-Ser-Asp-X 1 -X 2 -Phe-Thr-Asp-X 3 -X 4 -X 5 -X 6 -
X 7 -Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-
X 8 -X 9 -X 10 -X 11 (-X 12 );
(viii)
His-Ser-Asp-X 1 -X 2 -Phe-Thr-Asp-X 3 -X 4 -X 5 -X 6 -
X 7 -Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-
X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -
X 19 -X 20 -X 21 -X 22 ;
wherein X 1 -X 22 is any naturally occurring amino acid residue.
26 . A pharmaceutical composition comprising a peptide or polypeptide as specified in any of the claims 22 - 25 together with pharmaceutically acceptable carrier diluent or excipient.
27 . A method for treatment of a disease or a disorder correlated directly or indirectly with hypertension symptoms in human lung and/or heart tissue comprising administering to a patient a peptide or a polypeptide comprising the following amino acid sequence:
Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu.
28 . A method according to claim 27 , wherein said peptide or a polypeptide further comprises at least one of the following amino acid sequences:
His-Ser-Asp; Phe-Thr-Asp.
29 . A method according to claim 27 , wherein said peptide or a polypeptide has the following amino acid sequence:
(A) n -Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-(B) m wherein A, B is any natural occurring amino acid residue, A and B are independently from each other; and n, m is an integer having values from 0-25, n and m are independently from each other.
30 . A method according to claim 29 , wherein, if n>2, (A) n has the following sequence:
(X) o -Phe-Thr-Asp-(Y) p wherein X, Y is any natural occurring amino acid residue, X and Y are independently from each other; and o, p is an integer having values from 0-11, o and p are independently from each other.
31 . A method according to claim 30 , wherein, if o>2, (X) o has the following sequence:
(X′) q -His-Ser-Asp-(X″) r wherein X′, X″ is any natural occurring amino acid residue, X′ and X″ are independently from each other; and r, q is an integer having values from 0-4, r and q are independently from each other.
32 . A method according to claim 29 , wherein the sequence of said peptide or polypeptide is selected from the following group:
(i)
Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu;
(ii)
Phe-Thr-Asp-X 1 -X 2 -X 3 -X 4 -X 5 -Arg-Lys-Gln-Met-
Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn
(iii)
Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-
Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-
Asn;
(iv)
Phe-Thr-Asp-Ser-Tyr-Ser-Arg-Tyr-Arg-Lys-Gln-
Met-Ala-Val-Lys-Lys-Tyr-Leu;
(v)
His-Ser-Asp-X 1 -X 2 -Phe-Thr-Asp-X 3 -X 4 -X 5 -X 6 -
X 7 -Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu;
(vi)
His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-
Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-
Leu,
(vi)
His-Ser-Asp-Gly-Ile-Phe-Thr-Asp-Ser-Tyr-Ser-
Arg-Tyr-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-
Leu;
(vii)
His-Ser-Asp-X 1 -X 2 -Phe-Thr-Asp-X 3 -X 4 -X 5 -X 6 -
X 7 -Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-
X 8 -X 9 -X 10 -X 11 (-X 12 );
(viii)
His-Ser-Asp-X 1 -X 2 -Phe-Thr-Asp-X 3 -X 4 -X 5 -X 6 -
X 7 -Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-
X 8 -X 9 -X 10 -X 11 -X 12 -X 13 -X 14 -X 15 -X 16 -X 17 -X 18 -
X 19 -X 20 -X 21 -X 22 ;
wherein X 1 -X 22 is any naturally occurring amino acid residue.
33 . A method according to any of the claims 27 - 32 , wherein any of said peptides or polypeptides is an analogue or derivative having the same biological function.
34 . A method according to any of claim 33 , wherein any of said peptides or polypeptides is an a stabilized form.
35 . A method according to any of the claims 27 - 34 for reducing the vessel tone of human pulmonary arterial rings comprising administering to a patient said peptide or a polypeptide.
36 . A method according to any of the claims 27 - 34 for reducing the intracellular free calcium concentration in human vascular smooth muscle cells (VSMC) comprising administering to a patient said peptide or a polypeptide.
37 . A method according to any of the claims 27 - 34 for reducing the proliferation of vascular smooth muscle cells (VSMC) of human pulmonary arterial vessels comprising administering to a patient said peptide or a polypeptide.
38 . A method of any of the claims 35 - 37 , wherein the disease is primary pulmonary hypertension (PPH).
39 . A method of any of the claims 35 - 37 , wherein said disease is chronic obstructive pulmonary disease (COPD)
40 . A method of claim 39 , wherein said chronic obstructive pulmonary disease is secondary pulmonary hypertension (SPH).
41 . A method of any of the claims 27 - 34 , wherein said disease is arteriolar hypertension.
42 . A method of claim 41 , wherein said arteriolar hypertension is associated with PPH.
43 . A method according to any of the claims 27 - 34 , wherein said disease is heart failure associated with PPH.
44 . A method according to any of the claims 38 , wherein the pulmonary arterial pressure is reduced to more than 20% after administration of any of said peptides or polypeptides.
45 . A method of claims 41 or 42 , wherein the diastolic blood pressure is reduced to 5-25% and the systolic blood pressure is reduced to 10-30% after administration of any of said peptides or polypeptides.Join the waitlist — get patent alerts
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