PPAR gamma agonists for treatment of multiple sclerosis
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Publication Number
US-9061020-B2
Publication Date
2015-06-23
Expiration Date
Abstract
Methods of treatment of multiple sclerosis (MS) with PPARγ agonists, and in particular with the compound of formula (I) known as INT131:
Core Innovation
The invention relates to a peroxisome proliferator-activated receptor gamma (PPAR) agonist, INT131, described as a compound of formula (I), for use in treating multiple sclerosis (MS), including relapsing/remitting MS (RRMS). The described approach emphasizes selective PPAR pathway activation, including anti-inflammatory gene activation and neuroprotective gene activation cascades.
The background and rationale connect the treatment concept to RRMS and experimental autoimmune encephalomyelitis (EAE). In the described EAE findings, INT131 reduces relapse and decreases CD45-positive leukocyte infiltration during acute neuroinflammation.
The invention further characterizes neuroprotection and central nervous system exposure associated with INT131. It reports delayed but substantial accumulation of INT131 in brain and spinal cord after blood-brain barrier (BBB) penetration, including data derived from radiolabeled [3H]INT131 with cerebrospinal fluid (CSF) measurements. The neuroprotective aim is presented as sparing gray matter, including thalamic gray matter atrophy as a progression marker.
Claims Coverage
The independent claim set includes four independent methods, each centered on administering a compound of formula (I) (INT131) or related variants (pharmaceutically acceptable salt, prodrug, or isomer) to treat RRMS, treat RRMS symptoms, provide neuroprotection related to gray matter atrophy, and treat neuroinflammation symptoms. Across the independent claims, the main inventive focus is the same compound/variant administration linked to specific clinical targets.
Treating relapsing and remitting multiple sclerosis by regular dosing of formula (I) compound
A method of treating RRMS by administering, at regular dosing intervals, a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, or isomer thereof.
Treating symptoms of relapsing and remitting multiple sclerosis by administering formula (I) compound
A method of treating the symptoms of RRMS by administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, or isomer thereof.
Providing neuroprotection to a patient with gray matter atrophy by administering formula (I) compound
A method of providing neuroprotection to a patient with gray matter atrophy by administering a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, or isomer thereof.
Treating symptoms of neuroinflammation by administering formula (I) compound
A method of treating the symptoms of neuroinflammation by administering to a patient a compound of formula (I) or a pharmaceutically acceptable salt, prodrug, or isomer thereof.
Collectively, the independent claims cover administration of the formula (I) compound (INT131) and its pharmaceutically acceptable variants to treat RRMS, treat RRMS symptoms, provide neuroprotection associated with gray matter atrophy, and treat symptoms of neuroinflammation.
Stated Advantages
INT131 reduces relapse in an EAE model.
INT131 decreases CD45-positive leukocyte infiltration during acute neuroinflammation.
INT131 shows delayed but substantial accumulation in brain and spinal cord after BBB penetration.
Neuroprotection is described as sparing gray matter, including reduction/sparing of thalamic gray matter atrophy as a progression marker.
Documented Applications
Use of INT131 (compound of formula (I)) for treating MS, including relapsing/remitting MS (RRMS).
Use of INT131 in a neuroinflammation context, supported by EAE findings involving relapse and CD45-positive leukocyte infiltration during acute neuroinflammation.
Use of INT131 for providing neuroprotection related to gray matter atrophy, including thalamic gray matter atrophy as a progression marker.
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