Cysteine protease inhibitors to treat traumatic brain injury and Alzheimer's disease

This technology describes cysteine protease inhibitors for the treatment of Alzheimer’s disease (AD) Traumatic Brain Injury, and Memory Loss.

Unmet Need: Disease-modifying therapy for Alzheimer’s disease, 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.

The Technology: Highly potent, selective small molecule calpain inhibitors for treating Alzheimer’s disease

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.

Applications:

• Disease-modifying therapeutic for AD
• Treatment of traumatic brain injury and other neurodegenerative conditions in which cysteine protease inhibitors play a role
• Model compounds for studying cysteine protease function

Advantages:

• High selectivity and potency
• Low in vivo toxicity
• Optimal pharmacokinetic properties
• Capable of rescuing synaptic plasticity and memory in a transgenic model of AD regardless of the severity of the plaque load
• Top candidates have IC¬50 < 100 nM, optimal cLogP and solubility
• Straightforward synthesis and optimal scalability

Lead Inventor:

Ottavio Arancio, M.D., Ph.D.

Patent Information:

Patent Status

Related Publications:

• Fà M, Zhang H, Staniszewski A, Saeed F, Shen LW, Schiefer IT, Siklos MI, Tapadar S, Litosh VA, Libien J, Petukhov PA, Teich AF, Thatcher GR, Arancio O. “Novel selective calpain 1 inhibitors as potential therapeutics in Alzheimer’s disease” J Alzheimers Dis. 2016; 49(3): 707-721.

• Schiefer IT, Tapadar S, Litosh V, Siklos M, Scism R, Wijewickrama GT, Chandrasena EP, Sinha V, Tavassoli E, Brunsteiner M, Fà M, Arancio O, Petukhov P, Thatcher GR. “Design, synthesis, and optimization of novel epoxide incorporating peptidomimetics as selective calpain inhibitors” J Med Chem. 2013 Jul 8; 56(15): 6054-6068.

• Trinchese F, Fà M, Liu S, Zhang H, Hidalgo A, Schmidt SD, Yamaguchi H, Yoshii N, Mathews PM, Nixon RA, Arancio O. “Inhibition of calpains improves memory and synaptic transmission in a mouse model of Alzheimer disease” J Clin Invest. 2008 Jul 1; 118(8): 2796-2807.

Tech Ventures Reference:

• IR CU12222

• Licensing Contact: Ron Katz