Beta-hairpin peptidomimetics as selective elastase inhibitors
Inventors
Gombert, Frank Otto • Obrecht, Daniel • Sellier-Kessler, Odile • Lederer, Alexander • Ludin, Christian • SCHMITT-BILLET, Manuella • Weinbrenner, Steffen
Assignees
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Publication Number
US-10273267-B2
Publication Date
2019-04-30
Expiration Date
Abstract
β-Hairpin peptidomimetics of the general formula cyclo(-Xaa1-Xaa2-Thr3-Xaa4-Ser5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-) and pharmaceutically acceptable salts thereof, with Xaa1, Xaa2, Xaa4, Xaa6, Xaa7, Xaa8, Xaa9, Xaa10, Xaa11, Xaa12 and Xaa13 being amino acid residues of certain types which are defined in the description and the claims, have elastase inhibitory properties, especially against human neutrophil elastase, and can be used for preventing infections or diseases related to such infections in healthy individuals or for slowing infections in infected patients. The compounds of the invention can further be used where cancer, or immunological diseases, or pulmonary diseases, or cardiovascular diseases, or neurodegenerative diseases, or inflammation, or diseases related to inflammation, are mediated or resulting from elastase activity. These peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.
Core Innovation
The invention relates to backbone cyclized peptidic compounds of 13 amino acid residues according to the general formula cyclo(-Xaa1-Xaa2-Thr3-Xaa4-Ser5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-) and pharmaceutically acceptable salts thereof. The compounds are defined by specific residue identities at the Xaa positions, including alternative residue identities and modified moieties within the cyclized structure, together with multiple proviso constraints. The described compounds are presented as a constrained structural space for the backbone cyclized peptidic compounds.
The patent describes the compounds as elastase/protease inhibitors with selectivity against human neutrophil elastase and low activity toward proteinase 3. It also states unexpected low activity toward porcine pancreatic elastase, and attributes the activity and selectivity profile to the choice of residues and their positions within the β-hairpin peptidomimetic structure. β- and γ-amino acid elements are described as structural components that enhance resistance to proteolysis while maintaining the favorable activity/selectivity profile.
The patent provides defined cyclized peptide compound examples through an enumerated selection of cyclo(-...) sequence variants that fall within the described residue scope. The described compounds correspond to the general formula framework and its allowable residue identities and modifications.
Claims Coverage
The document provides two independent claims: one directed to a backbone cyclized 13-residue peptidic compound of general formula (I) with specified position-by-position residue options and multiple proviso constraints, including a conditional proviso when Xaa11 is Tyr, and another directed to a selected set of specific cyclo(-...) compound variants. Overall, the inventive coverage is structured as a formula-based compound scope with conditional residue constraints and an explicit selection of cyclo(...) sequence variants.
Backbone cyclized peptidic compound of general formula (I)
A backbone cyclized peptidic compound built up from 13 amino acid residues of the general formula cyclo(-Xaa1-Xaa2-Thr3-Xaa4-Ser5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-) (I), and pharmaceutically acceptable salts thereof, wherein Xaa positions are restricted to specified residue identities.
Multiple proviso constraints including conditional restriction when Xaa11 is Tyr
The compound further satisfies multiple proviso constraints that govern which residue identities may co-occur, including a further proviso that if Xaa11 is Tyr then Xaa1 is Dab(Phe); Arg; or Glu(Phe), and/or Xaa2 is Dap(Phe).
Selected cyclized peptide sequence variants as an enumerated compound set
A compound selected from the listed cyclo(-...) sequence variants, each written with specific residue constituents and modifications, including positions using OctGly, Dab(Phe), Glu(Phe), AllylGly, Nglu, Nlys, Pip, Azt, Oic, hSer/hSer(Me), hTyr, Thr/alloThr, Asn, diHTyr/diHThr dihydroxy-variants, H-β3-HGln-OH, H-β3-HLys-OH, H-β4-DiHTyr-OH, H-β4-DiHThr-OH, and combinations involving D-Pro/D-Ala/D-Val/D-Tyr/D-Lys/D-Ser and Pro/Oic variants.
Across the independent claims provided, coverage is based on backbone cyclized 13-residue peptidic compounds of general formula (I) with defined residue options at Xaa1-Xaa13 plus multiple proviso constraints, and on an enumerated selection of specific cyclo(-...) compound variants corresponding to particular allowed residue and modification combinations.
Stated Advantages
Elastase inhibitory properties with key selectivity against human neutrophil elastase.
Low activity toward proteinase 3.
Unexpected low activity toward porcine pancreatic elastase.
Resistance to proteolytic degradation associated with β- and γ-amino acid elements.
Documented Applications
Preventing elastase-mediated infections/diseases in healthy individuals.
Slowing infections in patients.
Applications where elastase activity mediates cancer, immunological diseases, pulmonary diseases, cardiovascular diseases, neurodegenerative diseases, and inflammatory diseases.
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