Design and Mechanism of (S)-3-Amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic Acid, a Highly Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Addiction

Abstract

γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. Inhibition of GABA aminotransferase (GABA-AT), a pyridoxal 5'-phosphate (PLP)-dependent enzyme that degrades GABA, has been established as a possible strategy for the treatment of substance abuse. The raised GABA levels that occur as a consequence of this inhibition have been found to antagonize the rapid release of dopamine in the ventral striatum (nucleus accumbens) that follows an acute challenge by an addictive substance. In addition, increased GABA levels are also known to elicit an anticonvulsant effect in patients with epilepsy. We previously designed the mechanism-based inactivator (1S,3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (2), now called CPP-115, that is 186 times more efficient in inactivating GABA-AT than vigabatrin, the only FDA-approved drug that is an inactivator of GABA-AT. CPP-115 was found to have high therapeutic potential for the treatment of cocaine addiction and for a variety of epilepsies, has successfully completed a Phase I safety clinical trial, and was found to be effective in the treatment of infantile spasms (West syndrome). Herein we report the design, using molecular dynamics simulations, synthesis, and biological evaluation of a new mechanism-based inactivator, (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (5), which was found to be almost 10 times more efficient as an inactivator of GABA-AT than CPP-115. We also present the unexpected crystal structure of 5 bound to GABA-AT, as well as computational analyses used to assist the structure elucidation process. Furthermore, 5 was found to have favorable pharmacokinetic properties and low off-target activities. In vivo studies in freely moving rats showed that 5 was dramatically superior to CPP-115 in suppressing the release of dopamine in the corpus striatum, which occurs subsequent to either an acute cocaine or nicotine challenge. Compound 5 also attenuated increased metabolic demands (neuronal glucose metabolism) in the hippocampus, a brain region that encodes spatial information concerning the environment in which an animal receives a reinforcing or aversive drug. This multidisciplinary computational design to preclinical efficacy approach should be applicable to the design and improvement of mechanism-based inhibitors of other enzymes whose crystal structures and inactivation mechanisms are known.

Progress report on new antiepileptic drugs: A summary of the Fourteenth Eilat Conference on New Antiepileptic Drugs and Devices (EILAT XIV). I. Drugs in preclinical and early clinical development

“…In vitro studies demonstrate time‐ and concentration‐dependent inhibition of GABA‐T, with inhibitory activity more than two orders of magnitude greater than vigabatrin (IC 50 = 0.28 and 58.5 μmol/L, respectively). Reduced ornithine transaminase activity was also observed in vitro, although this was 44‐fold less relative to GABA‐T . Separate from this, no appreciable binding of OV329 to any of the 176 targets included in the Cerep Spectrum Screen was observed at 3 μmol/L.…”

“…In vitro studies demonstrate time-and concentration-dependent inhibition of GABA-T, with inhibitory activity more than two orders of magnitude greater than vigabatrin (IC 50 = 0.28 and 58.5 μmol/L, respectively). Reduced ornithine transaminase activity was also observed in vitro, although this was 44fold less relative to GABA-T. 47 Separate from this, no appreciable binding of OV329 to any of the 176 targets included in the Cerep Spectrum Screen was observed at 3 μmol/L. Consistent with findings for vigabatrin, a single dose of OV329 (0.1 mg/kg ip) blocked cocaine-induced striatal dopamine release and hippocampal glucose activity in freely moving rats, providing in vivo evidence for target engagement.…”

“…Through inactivation of GABA‐T, the enzyme responsible for catabolism of GABA to succinic semialdehyde, OV329 increases GABA transmission and inhibits neuronal activity …”

Hemostatic Effect and Safety of TXA: An Umbrella Review

“…Suitable for lung, liver, pancreas, prostate, thyroid, adrenal gland surgery abnormal bleeding, obstetrics and gynecology and postpartum hemorrhage and pulmonary tuberculosis hemoptysis, sputum with blood, hematuria, prostate hypertrophy bleeding, upper gastrointestinal bleeding and so on. It has a signi cant effect on chronic blood oozing [147]. (3) the mechanism of aminocycline (hemostatic cyclic acid, thrombotic acid) is the same as TXA, and its effect is slightly stronger than that of aminomethylbenzoic acid.…”

1,4‐Disubstituted‐1,2,3‐triazole GABA Analogues: Synthesis, In Vitro Evaluation, Quantum QSAR and Molecular Docking against Pseudomonas fluorescens GABA‐AT

“…The design of analogues with fluorine atoms, led to CP‐115 2 , a cyclic compound 186 times more efficient than Vigabatrin 1 , as a GABA‐AT inactivator with a high therapeutic potential for the treatment of epilepsies and cocaine addiction . Later on, they reported 3 , a compound in turn 10 times more efficient than 2 , that suppresses the release of dopamine after a cocaine or nicotine dose in rats …”