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Non-natural amino acids and neurotensin analogues

Non-natural amino acids and neurotensin analogues description/claims

This patent application is a continuation-in-part of U.S. Ser. No. 11/629,806, filed Dec. 15, 2006, and presently pending, which is a U.S. national stage entry under 35 U.S.C. §371 from PCT/US2005/021580, filed Jan. 17, 2005, and published as WO2006/009902 A2 on Jan. 26, 2006, which claims the benefit of priority of U.S. provisional application Ser. No. 60/581,333, filed Jun. 17, 2004; all of which are herein incorporated by reference.

The influence that some non-natural amino acids have on the structural and biological activity of peptides has been briefly studied. For example, Moore et al. (Can. J. Biochem. 1978, 56, 315) disclosed the effect of the basic amino acid side chain length and the penultimate residue on the hydrolysis of benzoyldipeptides by carboxylicpeptidase B1 (CPB). Non-natural amino acids including homolysine and homoarginine were incorporated into small peptide chains, and the kinetic parameters were determined for the CPB catalyzed hydrolysis of the peptide. Also, Lindeberg et al. (Int. J. Peptide Protein Res. 1977, 10, 240) disclosed the synthesis of 1-deamino-4-L-valine-8-DL-homolysine-vasopressin and protected 1-deamino-4-L-valine-8-D-lysine-vassopressin in which non-natural amino acids were incorporated. The non-natural amino acids were formed by addition of a methylene group to lysine and arginine to generate the non-natural amino acids homolysine and homoarginine, respectively. The study revealed that peptides with homolysine and homoarginine reduced the antidiuretic activity of the peptides.

Naturally occurring endogenous peptides are ideal drug candidate leads by virtue of their myriad activities in promoting and regulating biological processes. Inherent in the chemistry and biology of peptides, however, are several factors that also make them poor drug candidates. Peptides most often exert localized effects and are rapidly degraded within the body. In addition, most peptides are unable to cross biological membranes, including the small intestine and blood brain barrier (BBB). Finally, peptides often bind to more than one receptor or receptor subtype, thus rarely showing the selectivity required of a viable drug candidate. Therefore, for a peptide to become a viable drug candidate, improvements in blood stability, receptor selectivity, and barrier crossing should be made without eliminating inherent binding affinity.

Numerous strategies have been developed as methods for improving peptide stability, including N- and C-terminal modifications to prevent exopeptidase activity, amide backbone modifications, and the introduction of conformational constraints to disguise peptides from peptidase degradation. Other therapeutic compounds employ a prodrug moiety intended to modify its overall hydrophobicity, which can result in the compound crossing biological membranes. In this case, the compound is cleaved into its active component by endogenous enzymes. While each of these strategies has been used to improve peptides as drug candidates, a universal solution for creating stable, receptor-selective peptides that cross biological barriers has not been discovered.

Consequently, there is a need in the art for non-natural amino acids and for peptides incorporating such acids to achieve superior effects, such as, for example, improved diagnostic or disease fighting activity. Thus, the non-natural amino acid concept could be applied to development of new peptide pharmaceuticals. One example of such a development is the application to neuropeptides such as neurotensin. Neurotensin (NT) is a 13-amino acid residue peptide found primarily in the brain. It has multifunctional activities manifested through binding and activation of two neurotensin receptors (NTRs), NTR-1 and NTR-2 (see Carraway & Leeman, J. of Biol. Chem. 248: 6854 (1973)). Although full activity of NT resides in its C-terminal six amino acid sequence (NH2-Arg(8)-Arg(9)-Pro(10)-Tyr(11)-Ile(12)-Leu(3)-COOH, designated NT[8-13], see Carraway & Leeman, J. Biol. Chem. 250:1907 (1975)), the C-terminal six amino acid sequence does not have activity when administered IP or orally due to its instability in blood and inability to cross the blood brain and/or gut barrier.

The present invention concerns alpha-desamino amino acid compounds (desamino amino acid compounds) that are capable of carrying positively charged side chains, their synthesis, their application as substitutes for natural amino acid moieties of biologically active peptides and the resulting peptides as well. In particular, alpha-desamino arginine, lysine and ornithine as well as their substituted and derivatized side chain analogs constitute preferred embodiments of the invention. These desamino amino acid compounds can be substituted for arginine and/or lysine moieties in any known, biologically active peptide such that the substituted peptide will be truncated at the substitution position. Alternatively, these desamino amino acid compounds can be coupled to the amino group of the N-terminus of any known biologically active peptide to produce an extended peptide. The truncated and extended peptides have significant biological selectivity and biological half lives owing to their resistance toward amino peptidase degradation.

In a first aspect, the invention relates to a non-natural desamino amino acid compound having Formula I:

wherein

n is an integer of from 0 to 5, preferably, 2 to 5;

m is zero or an integer of 1;

R is H or an organic substituent such as a straight or branched chain alkyl group of C1-C6, or an aromatic group of C6-C18 or a corresponding substituted aromatic group with one or two substituents selected from halogen, alkyloxy, carboxy, amide or alkyl in any combination, or a heteroaromatic group of C4-C18 and one or two heteroatoms selected from oxygen, sulfur and nitrogen in any combination or a corresponding substituted heteraromatic group with one or two substituents selected from halogen, alkyloxy, carboxy, amide or alkyl in any combination;

R1, R2, and R3 are, independently, hydrogen or branched or straight chain alkyl, alkenyl or alkynyl of C1-C6 or an aromatic group of C6-C18 or a corresponding substituted aromatic group with one or two substituents selected from halogen, alkyloxy, carboxy, amide or alkyl in any combination, or a heteroaromatic group of C4-C18 and one or two heteroatoms selected from oxygen, sulfur and nitrogen in any combination or a corresponding substituted heteraromatic group with one or two substituents selected from halogen, alkyloxy, carboxy, amide or alkyl in any combination and with the proviso that a maximum of two of R1, R2, and R3 may be selected to be the aromatic, substituted aromatic, heteroaromatic or substituted heteroaromatic group, and provided that when m is 0 or 1 and n is 0 to 5, R1, R2, and R3 are not all H;

Cα is a carbon atom having either R or S stereochemistry if the substituent at R is an organic substituent;

or an ester, amide, alkyl amide or metal cation or ammonium salt of the carboxylic acid group thereof, or an organic or inorganic acid salt of the amine group thereof, or any combination thereof.

In a second aspect, the invention relates to a non-natural desamino amino acid compound of the formula II:

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