SK channel positive allosteric modulators
Inventors
Zhang, Miao • Parang, Keykavous • Ibrahim, Naglaa • NAM, Young Woo • Bezprozvanny, Ilya • Cui, Meng
Assignees
Northeastern University Boston • University of Texas System • Chapman University
Publication Number
US-12312333-B2
Publication Date
2025-05-27
Expiration Date
2042-09-29
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Abstract
A compound according to Formula (I) or a pharmaceutically acceptable salt thereof: is provided. X1 is N or C—Y; Y is H, halogen, NH2, OH, SH, alkyl, aryl, alkoxy, or aryloxy; A is O, NH, S, Se, or CH2, B is X2 is N or CH; and Z is NH, CH2, S, O, or Se.
Core Innovation
The invention provides compounds of Formula (I) and pharmaceutically acceptable salts thereof, which are small molecule SK (small-conductance Ca2+-activated K+) channel positive allosteric modulators. It also discloses methods of preparing these compounds and their use in potentiating SK channels. Through structure-guided design and chemical synthesis, a series of novel CyPPA analogs with modifications at different ring systems were produced and evaluated for their ability to enhance KCa2.2a channel activity, exhibiting improved potency and maintained subtype selectivity.
The problem addressed is the need for potent and selective modulators of small conductance calcium-activated potassium (SK) channels, particularly KCa2.2 (SK2), which are involved in important physiological processes such as pacemaking of cerebellar Purkinje cells. Existing modulators, like CyPPA, show limited clinical fitness due to their low potency and incomplete subtype selectivity. There have also been challenges with binding site knowledge, which has hindered the development of more potent and effective therapeutics targeting these channels.
The core technological advance is the identification and synthesis of new CyPPA derivatives that, through specific substitutions on the phenyl, pyrimidine, and pyrazole rings, show significantly increased potentiation of SK2/SK3 channel activity with notable subtype selectivity. These compounds, such as 2o and 2q, exhibit up to 10-fold increased potency compared to CyPPA and normalize abnormal firing patterns in Purkinje cells in a mouse model of spinocerebellar ataxia, demonstrating their therapeutic potential in treating symptoms of ataxia and other movement disorders linked to SK channel dysfunction.
Claims Coverage
There is one independent claim in the patent, covering key chemical entities and compositions relating to SK channel modulation.
Compound according to Formula (Ia) or a pharmaceutically acceptable salt thereof
The main inventive feature is a compound having the structure defined as Formula (Ia) or its pharmaceutically acceptable salt, where: - X1 is N or C—Y (Y is H, halogen, NH2, OH, SH, alkyl, aryl, alkoxy, or aryloxy). - A is O, NH, S, Se, or CH2. - X2 is N or CH. - Z is NH, CH2, S, O, or Se. - Additional claims specify particular substituent patterns, e.g., X1, X2, X3, X4, X5, Y1, Y2, Z1, Z2, and Z3 as set forth for individual compound embodiments (e.g., specific halogen or alkyl substitutions). This feature encompasses not only the base chemical structure but also specific derivatives designed for selectively potentiating KCa2.2a/KCa2.3 channels.
The independent claim broadly covers Formula (Ia) compounds and their pharmaceutically acceptable salts, including a range of specifically substituted derivatives relevant to SK channel potentiation.
Stated Advantages
The compounds exhibit greatly improved potency for potentiating KCa2.2a channels compared to the parent template CyPPA.
Selective modulation of KCa2.2a and KCa2.3 channels while sparing KCa2.1 and KCa3.1 channels, reducing off-target effects.
Newly developed compounds can normalize abnormal firing of Purkinje cells in models of spinocerebellar ataxia, indicating potential therapeutic benefits for ataxia.
Documented Applications
Potentiation of SK (small conductance calcium-activated potassium) channel activity in subjects in need thereof.
Treatment of diseases and/or disorders associated with potassium channel activity, including neurodegenerative and neurological conditions such as Parkinson's disease, tremors, Alzheimer's disease, dementia, amyotrophic lateral sclerosis (ALS), ataxia, anxiety, depression, mood disorders, memory and attention deficits, bipolar disorder, psychosis, schizophrenia, traumatic brain injury, and narcolepsy.
Treatment of movement disorders, including spinocerebellar ataxia and essential tremor.
Treatment of heart disease and related conditions, metabolic disease, bladder diseases, withdrawal symptoms associated with addiction, respiratory diseases, epilepsy, convulsions, seizures, vascular spasms, renal disorders, erectile dysfunction, secretory diarrhea, ischemia, migraine, pain, and other conditions associated with potassium channel modulation.
Methods for modulating activity of a potassium channel in a subject, including positive modulation of SK channels in cells.
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