An imbalance in the levels of the inhibitory neurotransmitter g-aminobutyric acid (GABA) and the excitatory neurotransmitter glutamate can lead to convulsions. Inhibition of g-aminobutyric acid aminotransferase (GABA-AT), the enzyme responsible for the degradation of GABA, increases the GABA levels, which has been shown to produce an anticonvulsant effect. A sharp rise in dopamine release is associated with a variety of addictive behaviors. This dopamine release can be attenuated by an increase in GABA; therefore, inactivation of GABA-AT also has an effect on addictive behavior. Inactivation of a related enzyme, ornithine aminotransferase (OAT) in hepatocellular carcinoma (HCC) has been shown to slow the growth of this cancer. In this lecture the design and mechanism of some of our GABA-AT inactivators will be discussed and how these compounds led to the design and discovery of CPP-115, a potent inactivator of GABA-AT, which has been found to have excellent pharmacokinetic and pharmacological properties for the potential treatment of epilepsy and addiction. CPP-115 also inactivates OAT and has been shown to slow the growth of HCC. A related analogue of CPP-115 was identified that does not inactivate GABA-AT but is a potent inactivator of OAT. Another analogue of CPP-115 has been designed that is 10 times more potent than CPP-115. Enzyme inactivation mechanism studies will be discussed, as well as in vitro and in vivo efficacy and pharmacokinetic results, toxicology studies, including an early clinical trial with CPP-115.

<b>Award Address</b> (ACS Award for Creative Invention sponsored by ACS Corporation Associates). CPP-115: A novel GABA aminotransferase inactivator and potential new treatment for epilepsy, addiction, and hepatocellular carcinoma

253rd National Meeting (2017)

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Award Address (ACS Award for Creative Invention sponsored by ACS Corporation Associates). CPP-115: A novel GABA aminotransferase inactivator and potential new treatment for epilepsy, addiction, and hepatocellular carcinoma