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US 7,253,146 B2Granted
Template-fixed peptidomimetics with antimicrobial activity
AssigneePolyphor AG
InventorsDaniel Obrecht, John Anthony Robinson, Jan Wim Vrijbloed
Life of this patent
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AssigneePolyphor AG
InventorsDaniel Obrecht, John Anthony Robinson, Jan Wim Vrijbloed
Estimating the term…
Template-fixed β-hairpin peptidomimetics of the general formulae (I) and (II) wherein Z, Z1 and Z2 are template-fixed chains of 8 to 16 α-amino acid residues which, depending on their positions in the chain (counted starting from the N-terminal amino acid) are Gly, or Pro, or of certain types which, as the remaining symbols in the above formulae, are defined in the description and the claims, and salts thereof, have the property to inhibit the growth of or to kill microorganisms and cancer cells. They can be used as disinfectants for foodstuffs, cosmetics, medicaments or other nutrient-containing materials or as medicaments to treat or prevent infections or diseases related to such infections and/or cancer. These β-hairpin peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy
Compounds of the general formulae
Dependencies are inferred from the claim text.
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From the US filing history. Foreign family members aren’t listed.
Linear peptides containing only normal peptide links: having 5 to 11 amino acids
Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
Antineoplastic agents
On carriers: simultaneous synthesis of different peptide species; Peptide libraries
Term ended 18 Feb 2022 (estimated)
This application is the national stage filing under 35 U.S.C. §371 of PCT/EP02/01711, filed Feb. 18, 2002, which claims priority to PCT/EP01/02072, filed Feb. 23, 2001, both of which are incorporated by reference.
1. Field of the Invention
The present invention provides template-fixed β-hairpin peptidomimetics incorporating template-fixed chains of 8 to 16 α-amino acid residues which, depending on their positions in the chains, are Gly or Pro, or of certain types, as defined hereinbelow. These template-fixed β-hairpin mimetics have broad spectrum antimicrobial and anticancer activity. In addition, the present invention provides an efficient synthetic process by which these compounds can, if desired, be made in parallel library-format. These β-hairpin peptidomimetics show improved efficacy, bioavailability, half-life and most importantly a significantly enhanced ratio between antibacterial and anticancer activity on the one hand, and hemolysis of red blood cells on the other.
As used in this description, the term “alkyl”, taken alone or in combinations, designates saturated, straight-chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms. Similarly, the term “alkenyl” designates straight chain or branched hydrocarbon radicals having up to 24, preferably up to 12, carbon atoms and containing at least one or, depending on the chain length, up to four olefinic double bonds. The term “lower” designates radicals and compounds having up to 6 carbon atoms. Thus, for example, the term “lower alkyl” designates saturated, straight-chain or branched hydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl and the like. The term “aryl” designates aromatic carbocyclic hydrocarbon radicals containing one or two six-membered rings, such as phenyl or naphthyl, which may be substituted by up to three substituents such as Br, Cl, F, CF3, NO2, lower alkyl or lower alkenyl. The term “heteroaryl” designates aromatic heterocyclic radicals containing one or two five- and/or six-membered rings, at least one of them containing up to three heteroatoms selected from the group consisting of O, S and N and said ring(s) being optionally substituted; representative examples of such optionally substituted heteroaryl radicals are indicated hereinabove in connection with the definition of R77.
The structural element -A-CO— designates amino acid building blocks which in combination with the structural element —B—CO— form templates (a1) and (a2). Templates (a) through (p) constitute building blocks which have an N-terminus and a C-terminus oriented in space in such a way that the distance between those two groups may lie between 4.0–5.5 A. A peptide chain Z, Z1 or Z2 is linked to the C-terminus and the N-terminus of the templates (a) through (p) via the corresponding N- and C-termini so that the template and the chain form a cyclic structure such as that depicted in formula Ia. In a case as here where the distance between the N- and C-termini of the template lies between 4.0–5.5 A the template will induce the H-bond network necessary for the formation of a β-hairpin conformation in the peptide chain Z, Z1 or Z2. Thus template and peptide chain form a β-hairpin mimetic. The β-hairpin mimetics can also be coupled through groups G1 and G2 and a linker unit L to form the dimeric constructs of formula Ib.
The β-hairpin conformation is highly relevant for the antibiotic and anticancer activities of the β-hairpin mimetics of the present invention. The β-hairpin stabilizing conformational properties of the templates (a) through (p) play a key role not only for antibiotic and anticancer activity but also for the synthesis process defined hereinabove, as incorporation of the templates near the middle of the linear protected peptide precursors enhance significantly cyclization yields.