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Publication Number
US-11311560-B2
Publication Date
2022-04-26
Expiration Date
Abstract
Provided herein are cyclic plasmenylethanolamines and plasmalogen precursors of formula A, wherein R1 and R2 are each, independently, a saturated, unsaturated, or polyunsaturated hydrocarbon group. Methods and uses thereof in the treatment of plasmalogen deficiency are also described. Cyclic plasmenylethanolamines described herein may act as plasmalogen precursors which, following administration, may be converted to at least one plasmalogen species, thereby elevating the plasmalogen level in a subject.
Core Innovation
The invention concerns cyclic plasmenylethanolamine compounds of formula A and formula A′ as in vivo-convertible precursors for elevating plasmalogen levels in a subject. After administration in vivo, a compound of formula A or formula A′ is converted to at least one plasmalogen species, thereby elevating the plasmalogen level in the subject. The cyclic ethanolamine at sn-3 is described as improving vinyl-ether bond stability and providing potential late entry into the plasmalogen biosynthetic pathway.
The structural variability of the cyclic plasmenylethanolamine precursors is defined by substituents at sn-1 and sn-2, where each of R1 and R2 is independently a saturated, unsaturated, or polyunsaturated, optionally substituted hydrocarbon group. The hydrocarbon groups are described within a C1–C28 range and may include up to 6 double bonds. The precursor variants enter plasmalogen biosynthesis at different pathway stages and support sn-1/sn-2 remodeling and conversion to endogenous ethanolamine plasmalogen species.
Exemplary compounds include PPI-1040, PPI-1054, PPI-1056, PPI-1063, PPI-1045, and PPI-1046, which are compared to prior precursor PPI-1011 with limited augmentation. In Pex7 hypomorphic/null models, oral cyclic precursor PPI-1040 is described as bioavailable and as producing conversion and remodeling that increases endogenous ethanolamine plasmalogens, including a reported increase in 16:0/22:6. The same model context is described as showing improvement of a behavioral hyperactivity phenotype, together with functional data linking plasmalogen augmentation to increased long-term potentiation (LTP).
Claims Coverage
The document includes one independent claim focused on elevating plasmalogen levels by administering cyclic plasmenylethanolamine precursors of formula A or formula A′ in vivo, yielding conversion to plasmalogen species after administration. The main inventive features are further refined in dependent claims by limiting the substituent hydrocarbon groups at R1 and R2 and by specifying particular subject contexts and particular depicted formula-A structures.
In vivo plasmalogen elevation using formula A or formula A′ precursors
Administering in vivo to a subject in need thereof a therapeutically effective amount of at least one compound of formula A or formula A′, or a pharmaceutically acceptable salt or solvate, wherein following administration the compound is converted to at least one plasmalogen species, thereby elevating the plasmalogen level in the subject.
R1 and R2 as optionally substituted C1–C28 hydrocarbon groups
The method includes R1 and R2 each independently being an optionally substituted C1–C28 hydrocarbon group, with the administered compound converted after administration to at least one plasmalogen species for elevating plasmalogen levels.
Unsaturation-limited R1 and R2 with up to 6 double bonds
The method includes R1 and R2 independently each including up to 6 double bonds, with the administered compound converted after administration to at least one plasmalogen species for elevating plasmalogen levels.
R1 and R2 as fatty alcohol or fatty acid hydrocarbon chains
The method includes R1 and/or R2 being hydrocarbon chains of a fatty alcohol or fatty acid, with conversion after administration to at least one plasmalogen species to elevate plasmalogen levels.
Targeting plasmalogen elevation in RCDP or Zellweger spectrum disorder subjects
The method is applied to a subject having rhizomelic chondrodysplasia punctata (RCDP) or a Zellweger spectrum disorder, using the formula A or formula A′ compound to elevate at least one plasmalogen level.
Using depicted formula-A structures as the administered compounds
The method uses at least one compound of formula A comprising one or more of the depicted structures, or a pharmaceutically acceptable salt or solvate of the compound of formula A, for conversion after administration to plasmalogen species and elevation of plasmalogen levels.
Overall, the claim coverage centers on an in vivo plasmalogen-elevating method using cyclic precursor compounds of formula A or formula A′ that are converted after administration into plasmalogen species. The dependent claim refinements focus on the structural nature of the R1 and R2 substituent hydrocarbon groups, including optional substitution, C1–C28 range, limited double bonds, and fatty alcohol or fatty acid chain character, and on particular subject contexts and specific depicted formula-A structures.
Stated Advantages
Elevates at least one plasmalogen level in the subject after conversion of the administered formula A or formula A′ compound to plasmalogen species.
Improves endogenous ethanolamine plasmalogen levels in described Pex7 hypomorphic/null models.
Improves a behavioral hyperactivity phenotype in described Pex7 hypomorphic/null models.
Increases long-term potentiation (LTP) as a functional measure linked to plasmalogen augmentation.
Potential therapeutic use in plasmalogen-deficient neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.
Documented Applications
Elevating plasmalogen levels in subjects described as having plasmalogen deficiency.
Elevating plasmalogen levels in subjects with peroxisomal biogenesis disorder.
Elevating plasmalogen levels in subjects with rhizomelic chondrodysplasia punctata (RCDP) or a Zellweger spectrum disorder.
Potential therapeutic use in plasmalogen-deficient neurodegenerative diseases, including Alzheimer’s disease and Parkinson’s disease.
Treating plasmalogen deficiency.
Treating peroxisomal biogenesis disorders, including rhizomelic chondrodysplasia punctata (RCDP) and the Zellweger spectrum disorder.
Treating neurodegenerative indications including Alzheimer’s disease and Parkinson’s disease.
Increasing long-term potentiation (LTP) between neurons or in a subject.
Elevating plasmalogen levels in Pex7 hypomorph/null mice following oral administration of PPI-1040, with plasmalogen level changes toward normalization in plasma and selected peripheral tissues.
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