GABA, gamma-aminobutyric acid, is the chief inhibitory neurotransmitter in humans. It plays a role in regulating neuronal excitability throughout the nervous system. In humans, GABA is directly responsible for the regulation of muscle tone.
The precise mechanism of action for GABA transaminase or GABA-T (GABA-AT) inhibitors and their antiseizure effect is unknown, but it is believed to be the result of its action as an irreversible inhibitor of the enzyme GABA-AT, which is responsible for the metabolism and degradation of the inhibitory neurotransmitter GABA. This action results in increased levels of GABA in the central nervous system.
CPP-115 is one of a group of novel GABA-AT inhibitors discovered by scientists at Northwestern University. In 2009 Catalyst entered into a strategic collaboration with Northwestern University and in-licensed the worldwide rights to these inhibitors.
CPP-115 binds to GABA-AT, causing increased levels of GABA, the chief inhibitory neurotransmitter in humans. It plays a role in regulating neuronal excitability throughout the nervous system.
In preclinical studies CPP-115 has been shown to have potentially significant advantages compared to the only approved and marketed current GABA-AT inhibitor (vigabatrin). CPP-115 may not cause the visual field defects associated with chronic administration of vigabatrin, and it has been shown to be at least 200 times more potent in both in vitro and animal model studies. The increased potency could enable the development of superior or alternative dosage forms and routes of administration. Catalyst hopes these important benefits will allow it to develop CPP-115 for a broad range of other central nervous system indications, such as infantile spasms, epilepsy, Tourette’s syndrome and post-traumatic stress disorder (PTSD). Additionally, Catalyst is exploring other selected diseases in which modulation of GABA levels might be beneficial. Catalyst believes that it controls all current intellectual property for GABA-aminotransferase inhibitors.
CPP-115 has received orphan drug designation in the United States and orphan medicinal product designation in the European Union for infantile spasms. Catalyst has begun the clinical development of CPP-115 by completing a randomized, double-blind, single-ascending dose phase 1a study in normal healthy volunteers, to evaluate the human safety characteristics of CPP-115, including Central Nervous System (CNS) side effects and respiratory and cardiovascular safety. Results indicated that CPP-115 was well tolerated at all 6 doses administered up to 500 mg, well above the anticipated therapeutic dose of up to 80 mg/day.
CPP-109 (vigabatrin) is a first-generation GABA-aminotransferase (GABA-AT) inhibitor. It shares a common mechanism of action (inhibition of GABA-AT) with CPP-115. Vigabatrin is already approved for human use (Sabril®, Lundbeck), and Catalyst is employing CPP-109 as a research surrogate for exploring potential indications for which there are no adequate animal models. These conditions include, but are not limited to, PTSD and Tourette’s syndrome.
For more information about (GABA-AT) inhibitors including CPP-115, please choose from the list of clinical publications and reviews below.
Doumlele K, Conway E, Hedlund J, Tolete P, Devinsky O. A case report on the efficacy of vigabatrin analogue (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115) in a patient with infantile spasms. Epilepsy Behav Case Rep. 2016;6:67-69. Go to publication
Briggs SW, Mowrey W, Hall CB, Galanopoulou AS. CPP-115, a vigabatrin analogue, decreases spasms in the multiple-hit rat model of infantile spasms. Epilepsia. 2014; 55(1):94-102. Go to publication
Hawker DD, Silverman RB. Synthesis and evaluation of novel heteroaromatic substrates of GABA aminotransferase. Bioorg Med Chem. 2012;20(19):5763-5773. Go to publication
Pan Y, Gerasimov MR, Kvist T, et al. (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent γ-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction. J Med Chem. 2012;55(1):357-366. Go to publication
Yuan H, Silverman RB. Structural modifications of (1S,3S)-3-amino-4–difluoromethylenecyclopentanecarboxylic acid, a potent irreversible inhibitor of GABA aminotransferase. Bioorg Med Chem Lett.2007;17(6):1651–1654. Go to publication