An imbalance in the levels of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and the excitatory neurotransmitter L-glutamate can lead to convulsions. Inhibition of GABA aminotransferase (GABA-AT), the enzyme responsible for the degradation of GABA, increases brain GABA levels, which has been shown to produce an anticonvulsant effect. Reduced brain GABA concentration also is implicated in neuropathic pain. 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 GABA-AT inactivators will be discussed and how this led to the design and discovery of CPP-115 and OV329, potent inactivators of GABA-AT, which have been found to have excellent pharmacokinetic and pharmacological properties for the potential treatment of epilepsy and neuropathic pain. Several analogues related to CPP-115 were identified that do not inactivate GABA-AT but are potent inactivators of OAT. Enzyme inactivator design and mechanism studies will be discussed, as well as in vitro and in vivo efficacy and pharmacokinetic results, toxicology studies, and a clinical trial with CPP-115.

Novel GABA aminotransferase and ornithine aminotransferase inactivators and potential new treatments for epilepsy, neuropathic pain, and hepatocellular carcinoma

Fall 2022 abstracts, posters, and presentations will launch in mid-September.

ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.