Polypeptide protracting tags

The present invention relates to compounds comprising a heterocyclic carboxylic acid bioisostere, methods for preparing the compounds and the medical applications of such compounds.

It is often desirable to maintain well-defined concentrations of a given compound in the blood stream for a long time. This would for instance be the case when an immunogen is administered and a strong immune response is desired, or when a therapeutic target has to be exposed continuously to a therapeutic agent for a long time. Currently there are no universally applicable strategies to enhance the plasma half-life of any type of compound. The number of known endogenous polypeptides with interesting biological activities is growing rapidly, also as a result of the ongoing exploration of the human genome. Due to their biological activities, many of these polypeptides could in principle be used as therapeutic agents. Endogenous peptides are, however, not always suitable as drug candidates because these peptides often have half-lives of few minutes due to rapid degradation by peptidases and/or due to renal filtration and excretion in the urine. The half-life of polypeptides in human plasma varies strongly (from a few minutes to more than one week). Similarly, the half-life of small molecule drugs is also highly variable. The reason for this strong variability of plasma half-lives of peptides, proteins, or other compounds is, however, not well understood.

Serum albumin has a half-life of more than one week, and one approach to increasing the plasma half-life of peptides has been to derivatised the peptides with a chemical entity that binds to serum albumin.

Knudsen et al. (J. Med. Chem. 2000, 43, 1664-1669) have shown that acylated GLP-1 peptides exhibit high receptor potency and a tenfold increase of plasma half-life in pigs. Zobel et al. (Bioorg. Med. Chem. Lett. 2003, 13, 1513-1515) have shown that the plasma half-life of an anticoagulant peptide in rabbits increased by 10-50 fold on derivatisation of the amino terminus with phosphate ester based small molecules binding to serum albumin.

According to the present invention there is provided a method for increasing the plasma half-life of a molecule, comprising covalently linking this molecule to a heterocyclic carboxylic acid bioisostere.

The present invention also relates to a method for increasing the plasma half-life of a molecule, comprising covalently linking this molecule to a 1H-tetrazole.

According to the present invention there is also provided a method for increasing the plasma half-life of a molecule, comprising converting said molecule into a compound of the general formula (I):

wherein
G, X, and Y independently represent

• • a bond, —S—, —O—, —NH—, —(CH₂)_1-10—, or
  • arylene, optionally substituted with one or more alkyl, amino, cycloalkyl, aryl, heteroaryl, halogen, nitro, lower alkoxy, hydroxy, MeCONH—, alkanoyl, or cyano, or
  • heteroarylene, optionally substituted with one or more alkyl, amino, cycloalkyl, aryl, heteroaryl, halogen, nitro, lower alkoxy, hydroxy, MeCONH—, alkanoyl, or cyano, and
    
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