This technology describes cysteine protease inhibitors for the treatment of Alzheimer’s disease (AD) Traumatic Brain Injury, and Memory Loss.
There is an urgent need for therapeutics that could prevent the underlying cell death and synaptic dysfunction in traumatic brain injury, memory loss and AD. Calcium-activated neutral cysteine proteases (calpains) are a variegated cluster of calcium-dependent proteases that are broadly expressed. Over-activation of calpain 1 in particular, which is found in the synapses of neurons, has long been appreciated to contribute to neuropathological changes that impair synaptic transmission in AD patients, as well as patients who experienced traumatic brain injury. As such, selective targeting of calpain 1 presents an attractive approach to preventing the progression of AD and treatment of traumatic brain injury. However, the development of a class of molecules that are more selective has proved challenging.
This technology describes a novel class of epoxide-based inhibitors, synthesized to display improved selectivity and potency towards calpain 1 compared to the prototype epoxide-based generic calpain inhibitor E64. Two 3rd generation inhibitors, NYC438 and NYC488, were potent inhibitors of calpain 1 (IC50 <100 nM) with improved selectivity, demonstrated functional brain bioavailability, very good PK characteristics with a slightly longer half-life for NYC438 versus NYC488 (∼1.1 h and ∼0.6 h), and easy synthetic scalability. Calpain inhibition was able to recover the plasticity and the memory impairment associated with the exposure to shockwave induced traumatic brain injury and to Aβ42 in a mouse model of AD. The inhibitors, moreover, showed no overall toxicity, and therefore represent promising candidates for clinical trials of neurodegenerative diseases.
IR CU12222
Licensing Contact: Ron Katz