Synthetic peptide amides and dimers thereof
Inventors
Schteingart, Claudio D. • Menzaghi, Frédérique • Jiang, Guangcheng • Alexander, Roberta Vezza • Sueiras-Diaz, Javier • Spencer, Robert H. • Chalmers, Derek T. • Luo, Zhiyong
Assignees
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Publication Number
US-10913769-B2
Publication Date
2021-02-09
Expiration Date
Abstract
The invention relates to synthetic peptide amide ligands of the kappa opioid receptor and particularly to agonists of the kappa opioid receptor that exhibit low P450 CYP inhibition and low penetration into the brain. The synthetic peptide amides of the invention conform to the structure: The compounds are useful in the prophylaxis and treatment of pain and inflammation associated with a variety of diseases and conditions.
Core Innovation
The invention relates to a method of treating, inhibiting or preventing a kappa opioid receptor-associated disease or condition in a human patient or a mammal, wherein the disease or condition is pruritis or pruritus. The method comprises administering an effective amount of a composition comprising a synthetic peptide amide, or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, acid salt hydrate, or N-oxide thereof.
The synthetic peptide amide is defined by a highly specific formula that constrains peptide components through selections for Xaa1, Xaa2, and Xaa3-Xaa4, and by defined linker and substituent patterns. The heterocyclic ring moiety portion is specified as an optionally substituted 4 to 8-membered heterocyclic ring moiety with ring heteroatoms all being N, with constraints on Y and Z, ring separation for six-, seven-, or eight-membered rings, and a non-aromatic requirement in a single N-heteroatom case.
The structure further constrains W as null in defined cases or as NH-(CH2)b or NH-(CH2)c-O, and constrains V as C1-C6 alkyl with e being zero or 1. The substituents R1 and R2 are defined through structural relationships that permit directly bonded attachment, formation of optionally substituted 4- to 9-membered heterocyclic monocyclic or bicyclic rings, spiro structures, or fused heterocyclic rings, together with additional provisos restricting specific combinations under defined ring heteroatom patterns.
Claims Coverage
The independent claim scope is centered on treating, inhibiting or preventing kappa opioid receptor-associated pruritis or pruritus by administering a composition comprising a synthetic peptide amide of a highly defined structural formula. The inventive features cover the pruritis indication and the formula-defined peptide amide with constrained residue selections, heterocyclic ring parameters, and substituent relationships.
Kappa opioid receptor-associated pruritis treatment method
A method of treating, inhibiting or preventing a kappa opioid receptor-associated disease or condition in a human patient or a mammal, wherein the disease or condition is pruritis or pruritus, comprising administering to the human patient or the mammal a composition comprising an effective amount of a synthetic peptide amide of a specified formula, or a stereoisomer, mixture of stereoisomers, pharmaceutically acceptable salt, hydrate, acid salt hydrate, or N-oxide thereof.
Peptide amide residue selection and defined peptide portion
The synthetic peptide amide includes residue selections where Xaa1 is independently selected from specified D-amino acid options, Xaa2 is independently selected from specified residue options, and Xaa3-Xaa4 is selected from specified D-Nle/D-Leu and D-Arg/D-Orn-containing patterns.
N-heterocycle ring moiety with constrained Y/Z, ring size, and saturation/aromaticity
The synthetic peptide amide includes an optionally substituted 4 to 8-membered heterocyclic ring moiety wherein all ring heteroatoms are N, wherein Y and Z are each independently C or N with constraints tied to ring size, and wherein a single N-heteroatom ring moiety is non-aromatic.
Linker/segmenting variable W and alkyl/isomer variable V with e
The synthetic peptide amide constrains W to selected options including null, NH-(CH2)b, or NH-(CH2)c-O, and constrains V as C1-C6 alkyl with e being zero or 1, including a condition that when e is zero V is null and R1 and R2 are directly bonded to the same or different ring atoms.
R1/R2 substituent relationships enabling ring, spiro, or fused heterocycle structures
The synthetic peptide amide constrains R1 and R2 via permitted substituent sets and structural relationships, including configurations where R1 and R2 form optionally substituted 4- to 9-membered heterocyclic rings, spiro structures with a 4- to 8-membered heterocyclic ring, or fused monocyclic or bicyclic heterocyclic ring moieties.
Across the independent claim scope, the coverage centers on administering a composition containing a synthetic peptide amide for kappa opioid receptor-associated pruritis or pruritus, where the peptide residues and an N-only heterocyclic ring moiety are constrained through Y/Z, W, V/e, and R1/R2 structural relationships that allow ring, spiro, or fused configurations.
Stated Advantages
Treating, inhibiting or preventing a kappa opioid receptor-associated disease or condition in a human patient or a mammal.
Treatment specifically for pruritis or pruritus associated with kappa opioid receptor.
Higher sedative ED50 relative to analgesic ED50.
Low apparent membrane permeability.
Brain exposure lower than peak plasma exposure.
Sustained efficacy, described as 50% to 95% maximal efficacy at 3 hours.
Selective and/or peripherally acting with little or no CNS effects.
Sodium/potassium-sparing aquaresis.
Documented Applications
Treatment, inhibition, or prevention of kappa opioid receptor-associated pruritis or pruritus in a human patient or a mammal.
Uremic pruritis.
Chronic kidney disease-associated pruritis in a human patient or mammal undergoing hemodialysis.
Pruritis associated with atopic dermatitis, ocular pruritis, otic pruritis, insect bite pruritis, opioid-induced pruritis, and pruritis in cholestasis.
Treatment of hyponatremia and edema via sodium/potassium-sparing aquaresis.
Treatment indications described for neurodegenerative and ocular diseases, including glaucoma and intraocular pressure.
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