COMPOSITIONS AND METHODS FOR TREATMENT OF NEUROLOGICAL DISEASE

Field of the Disclosure Disclosed herein are monomethyl fumarates, pharmaceutical compositions including monomethyl fumarates, and methods of using the monomethyl fumarates and pharmaceutical compositions thereof for treating mitochondrial, neurodegenerative, inflammatory and autoimmune diseases including Leigh’s Syndrome, Leber’s Hereditary Optic Neuropathy, Mitochondrial Encephalomyopathy Latic Acid (MELAS), Myoclonic Epilepsy Red Ragged Fiber (MERRF), Friedreich’s ataxia, multiple sclerosis, various dementias, autism and psychological disorders. Fumarate acid esters are known to activate the Nrf2 pathway, which both activates the Antioxidant Response Element (ARE) and also results in dimethylfumarate triggered mitochondrial biogenesis. However, FAEs have notable dose limiting side effects including flushing, nausea, vomiting, gastrointestinal disturbances, and lymphopenia (Liang, Chai et al. 2020). Many FAE prodrugs have been prepared and evaluated (see, e.g., U.S. Pat. Nos. 6,436,992; 7,157,426; 7,320,999; 7,432,240; 8,669,281; 9,403,784; 9,409,872; 9,532,968; and 11,142,501). FAE prodrugs such as dimethylfumarate and diroximel fumarate (DRF) are rapidly metabolized to monomethylfumarate (MMF), and MMF is known to penetrate the blood brain barrier (BBB), with calculated Log([Brain]/[Blood]) of -1. However, MMF penetration into human CSF is experimentally only about 11% of the blood concentration (Edwards, Kamath et al. 2021), leaving the high peripheral blood concentration to cause unwanted side effects. In the case of mitochondrial diseases such as MELAS, MERRF and Leigh’s Syndrome, it is particularly desirable for the MMF to penetrate the CNS to exert the desired activation of the Nrf2 pathway and subsequent mitochondrial biogenesis with as high a concentration as can be tolerated. The BBB is a difficult barrier to penetrate even for small molecules. One approach to increasing the CNS penetration of MMF is to utilize a carrier molecule that utilizes active transport proteins, such as glucose transporter 1 (GLUT1), sodium vitamin C transporter 2 (SVCT2) (Nualart, Mack et al. 2014) or large neutral amino acid transporter 1 (LAT1) (Singh and Ecker 2018). Briefly, GLUT1 transports dehydroascorbic acid, but not ascorbic acid. Once transported into the brain, dehydroascorbic acid is reduced to ascorbic acid, and ascorbic acid is retained in the brain at a 10-fold concentration higher than the blood. SVCT2 transports ascorbic acid directly into the brain, while LAT1 transports amino acids into the brain. The same transporters are also involved in intestinal uptake (Fraga, Pinho et al. 2005, Cao, Gibbs et al. 2006, Subramanian, Srinivasan et al. 2017), simultaneously addressing the need for improved intestinal absorption to decrease nausea, vomiting and gastrointestinal disturbances. CNS penetrating prodrugs utilizing carriers (Rautio, Laine et al. 2008) such as reduced ascorbic acid (Manfredini, Pavan et al. 2002) for transporting Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are known (Zhao, Qu et al. 2014, Wang, Zhang et al. 2018), as are LAT1 utilizing carriers (Gynther, Laine et al. 2008). However, these carriers have not been applied to FAEs. There are examples of a fumarate ester with ascorbic acid for antimicrobial and agricultural applications (see CN Pat. No. 102,442,983), acrylate esters of dehydroascorbic acid (see JP Pat. No. 5,781,983) for agricultural applications, and threonine conjugates to many FDA-approved carboxylic acids (see U.S. Pat. No. 8,173,840). Due to the relatively small size of the FAEs, these are ideal candidates for transport into the brain using GLUT1, SVCT2 and LAT1. To address the urgent need for new therapeutics in the area of mitochondrial diseases, this disclosure provides enhanced BBB and intestinal penetrating-MMF prodrugs. In some preferred embodiments, these have been designed using dehydroascorbic acid, ascorbic acid and amino acids as carriers that result in a significant increase in brain MMF concentration and mitochondrial biogenesis activity. In some preferred embodiments, bulky functional groups have been added to provide steric hinderance and prevent unwanted FAE cleavage in the intestine and plasma, but leave GLUT1, SVCT2 and LAT1 substrate transport. These compounds that penetrate the CNS and trigger mitochondrial biogenesis are configured to have broad utility in human disease (Edeas and Weissig 2013). The compounds of the present disclosure, thus, provide a solution to the art-recognized problems discussed above. Other advantages will be clear to those of ordinary skill in the art from this disclosure.