Derivatives of CGRP
Inventors
Nielsen, Anette Sams • Kruse, Thomas • Kodra, Janos Tibor • Lau, Jesper F. • Kofoed, Jacob • Raun, Kirsten • Nilsson, Cecilia
Assignees
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Publication Number
US-8835379-B2
Publication Date
2014-09-16
Expiration Date
Abstract
Acylated CGRP compounds with a linker have prolonged action and are valuable as medicaments.
Core Innovation
The invention relates to acylated calcitonin gene-related peptide (CGRP) derivatives in which a CGRP compound (X) is connected through a linker (Y) to an acyl group (Z). X is a CGRP compound in which, formally, a hydrogen has been removed from one of the amino groups present in an amino acid residue, and the Y carbonyl end is connected to the CGRP compound while the Y amino end is connected to the acyl group Z. The —Y—Z moiety is connected to an amino group present at the N terminal amino acid residue of the CGRP.
The compounds are defined by linker Y selected from six groups of formulae, with m, n, s and p parameter ranges, and Z is an acyl group. The document describes defining the CGRP sequence scope across CGRP-alpha and CGRP-beta forms and across species, using conservative substitutions within the CGRP compound, and requiring preservation of disulfide features, including an intramolecular disulphide bridge between Cys residues. The acylation/linker design is presented as a way to achieve prolonged action.
The background and summary portions state that the aim is prolonged CGRP effects, and the document links this to metabolic syndrome-related pharmacology, including GLP-1 release, reduced food intake, weight loss, lowered blood pressure, improved insulin sensitivity and HbA1c, sustained vasodilation, and increased energy expenditure. Experimental evidence is described showing improved pharmacokinetics, elevated GLP-1 plasma levels, in vitro potency in cAMP accumulation/cAMP assays, and in vivo reductions in cumulative food intake and blood pressure, along with increased energy expenditure and food oxidation and reductions in HbA1c and fasting insulin in disease models.
Claims Coverage
The independent claim covers a CGRP-derived compound of formula X—Y—Z with inventive attachment architecture, where a selected linker connects a CGRP-derived X to an acyl group Z at the N-terminal amino group of the CGRP. Dependent claims refine specific CGRP sequence/formula embodiments, the acyl source constraints, the attachment point on the CGRP, and specific therapeutic use for metabolic and cardiovascular indications.
CGRP-linker-acyl architecture with N-terminal amino attachment
A compound comprising the formula X—Y—Z wherein X designates a calcitonin gene-related peptide (CGRP) compound from which, formally, a hydrogen has been removed from one of the amino groups present in an amino acid residue; Y is a linker elected from the group consisting of the six groups of the following formulae; wherein the carbonyl end of these moieties is connected to the CGRP compound and the amino end of these moieties is connected to the acyl group; and Z is an acyl group; wherein the —Y—Z moiety is connected to an amino group present at the N terminal amino acid residue of the CGRP compound.
Selected linker parameterized by m, n, s and p ranges
Y is a linker elected from the group consisting of the six groups of the following formulae, wherein m is 0, 1, 2, 3, 4, 5 or 6; n is 1, 2 or 3; s is 0, 1, 2 or 3; and p is 1 to 23.
Acyl group Z from a fatty acid or fatty diacid carbon-number range
Z is defined as an acyl group derived from a fatty acid or fatty diacid having 12 to 22 carbon atoms.
Linker-acyl moiety attached to a lysine residue
The —Y—Z moiety is attached to a CGRP compound at a lysine residue.
Therapeutic use by administration for metabolic and cardiovascular conditions
A method for treating diabetes, insulin resistance, obesity, hypertension, and cardiovascular disease by administering a therapeutically effective amount of a compound comprising the formula X—Y—Z of the claim to a subject in need.
Overall, the claim coverage centers on an acylated CGRP derivative in which a selected linker connects a CGRP-derived X to an acyl group Z, with the linker–acyl moiety attached to the CGRP N-terminal amino group. Dependent refinements specify linker parameter ranges, an acyl source carbon-number range, attachment to a lysine residue, and therapeutic use for diabetes, insulin resistance, obesity, hypertension, and cardiovascular disease.
Stated Advantages
Prolonged CGRP effects.
GLP-1 release.
Reduced food intake.
Weight loss.
Lowered blood pressure.
Improved insulin sensitivity and reduced HbA1c.
Sustained vasodilation.
Increased energy expenditure.
Documented Applications
Treatment of metabolic syndrome-related conditions including diabetes, insulin resistance, obesity, hypertension, and cardiovascular disease by administering therapeutically effective amounts of the disclosed compounds to a subject in need.
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