Compounds and compositions for the treatment of neurodegenerative and inflammatory diseases
Inventors
EL AMRI, CHAHRAZADE • SOUALMIA, FERYEL • MASURIER, NICOLAS • AÏT AMIRI, SABRINA • NAIT OUMESMAR, BRAHIM • DEBOUX, CYRILLE
Assignees
Centre National de la Recherche Scientifique CNRS • Assistance Publique Hopitaux de Paris APHP • Institut National de la Sante et de la Recherche Medicale INSERM • Ecole Nationale Superieure de Chimie de Montpellier ENSCM • Universite de Montpellier • Sorbonne Universite • Institut du Cerveau et de La Moelle Epiniere ICM
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Publication Number
US-11541023-B2
Publication Date
2023-01-03
Expiration Date
Abstract
The invention relates to compounds exhibiting kallikrein inhibitory activity, and to compositions comprising at least one of these compounds for use in the treatment of diseases or disorders in which kallikrein activity is dysregulated, particularly neurodegenerative and inflammatory diseases.
Core Innovation
The invention relates to kallikrein-inhibitory compounds defined by formula (I), including para-amidobenzylamine/2-hydroxybenzamide or naphthamide scaffold derivatives. The compounds are presented as optionally having an amino protective group used in peptide synthesis and as pharmaceutically acceptable salts. The subject matter is focused on compounds that inhibit kallikrein activity, in particular kallikrein-6 (KLK6), with associated effects on neural cell models.
The invention addresses diseases linked to dysregulation of kallikrein activity by providing methods for treatment through administering at least one compound of formula (I), or a pharmaceutical composition comprising the compound, to a subject in need thereof. The therapeutic rationale targets KLK6 and relates to neuroinflammatory and neurodegenerative contexts, including multiple sclerosis.
The disclosed compounds are characterized as reversible KLK6 inhibitors and are associated with anti-neurotoxic profiles in cell models. The reported observations include reduced neurocytotoxicity and increased promotion of oligodendrocyte precursor cell differentiation, including mCherry/mature marker and MBP+ differentiation for selected compounds.
Claims Coverage
The document includes two independent claims: an independent method claim and an independent pharmaceutical composition claim. Together, they cover administering formula (I) kallikrein-inhibitory compounds and formulating them as pharmaceutical compositions, with the same core structural framework for formula (I).
Treatment method using formula (I) kallikrein inhibitors
A method for the treatment of a disorder or a disease linked to a dysregulation of the activity of at least one kallikrein of a subject in need thereof, comprising administering at least one compound of formula (I) or a composition comprising said compound.
Pharmaceutical composition containing formula (I) compounds
A pharmaceutical composition comprising, in a pharmaceutically acceptable medium, at least one compound of formula (I).
Claim coverage is directed to formula (I) kallikrein-inhibitory compounds used either directly in a treatment method or incorporated into a pharmaceutical composition. Both claim categories maintain the same formula (I) framework, including the specified R5 and R6 definitions, optional amino protective group used in peptide synthesis, and/or pharmaceutically acceptable salts.
Stated Advantages
Compounds are described as reversible KLK6 inhibitors.
Compounds are associated with an anti-neurotoxic profile.
Compounds show reduced neurocytotoxicity in cell models.
Compounds promote oligodendrocyte precursor cell differentiation (mCherry/mature marker; MBP+ for compounds 3 and 4).
Documented Applications
Treatment of disorders or diseases linked to dysregulation of kallikrein activity, including CNS neurodegenerative and inflammatory disorders.
Treatment of cerebral ischemia.
Treatment of multiple sclerosis.
Treatment of Parkinson's disease.
Treatment of Alzheimer's disease.
Treatment of spinal cord lesions.
Treatment of pulmonary inflammation.
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