Compounds with the biological activity of vasoactive intestinal peptide for the treatment of pulmonary and arteriolar hypertension

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 remodeling 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 comprise 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 cyclase-activating 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.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation application of U.S. application Ser. No. 10 / 416,822 filed Oct. 3, 2003 which is the national stage entry of PCT application number PCT / EP01 / 13590 filed Nov. 22, 2001, which in turn stems from European Patent Application No. EP 00125935.7, each of which is incorporated by reference in its entirety.[0002]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 remodeling 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 comprise 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...

AI Technical Summary

Benefits of technology

[0022]Polypeptides or peptides, wherein (A)n (if n>2) comprises the tripeptide sequences His-Ser-Asp (SEQ ID NO: 14)- and / or Phe-Thr-Asp (SEQ ID NO: 13) in N-terminal direction near by (1-10 amino acid residues) above-specified decapeptide sequence have an enhanced activity.

[0050]The term “stabilized form” means a derivative or analogue wherein the parent peptide was altered in order get more stability and increased half-life in blood and serum. Such stabilized forms are preferred if the polypeptide is fragmented by enzyme activity. Possible stabilized forms are cyclic peptides or polypeptides like cyclic VIP or Vyclic PACAP, fusion proteins, preferably Fc-fusion proteins or pegylated polypeptides, for example pegylated VIP or PACAP. Methods for manufacturing such polypeptides are well known in the art. Polypeptides and proteins may be protected against proteolysis by the attachment of chemical moieties. Such attachment may effectively block the proteolytic enzyme from physical contact with the protein backbone itself, and thus prevent degradation. Polyethylene glycol is one such chemical moiety which has been shown to protect against proteolysis (Sada, et al., J. Fermentation Bioengineering 71: 137-139, 1991). In addition to protection against proteolytic cleavage, chemical modification of biologically active proteins has been found to provide additional advantages under certain circumstances, such as increasing the stability and circulation time of the therapeutic protein and decreasing immunogenicity. (U.S. Pat. No. 4,179,337; Abuchowski et al., Enzymes as Drugs.; J. S. Holcerberg and J. Roberts, eds. pp. 367-383, 1981; Francis, Focus on Growth Factors 3: 4-10; EP 0 401 384). The addition of polyethylene glycol increases stability of the peptides and polypeptides of this invention at physiological pH as compared to non-pegylated compounds. The pegylated polypeptide / protein is also stabilized with regard to salts.

[0051]The term “fusion protein” means a compound, especially a stabilized form, consisting of a polypeptide according to the invention, preferably VIP or a VIP derivative or analogue, such as PACAP, which is fused to another peptide or protein. Such a protein is preferably an immunglobulin molecule, more preferably a fragment thereof, most preferably a Fc portion of an IgG molecule, preferably an IgG1. A Fc-VIP fusion protein is described in WO 200024278 and shows an improved half-life in serum and blood. A further example is Fc-PACAP and FC-PACAP-27.

[0063]It is likely that the therapy with the compounds of the invention, alone or in combination with the above mentioned substances, may lower existing but undesired drug effects in a subject in need of those drugs.

Problems solved by technology

The therapy of pulmonary hypertension is unsatisfactory.

Although the vasodilation in numerous tissues, heart and lung tissue included, there is no clinical evidence up to now that VIP or PACAP are effective in the treatment of pulmonary hypertension in humans.

In particular, endothelial dysfunction leading to decreased bioavailability of nitric oxide impairs endothelium-dependent vasodilation in patients with essential hypertension and may also be a determinant for the premature development of atherosclerosis.

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