Subtype-selective GABA(A) receptor modulation yields a novel pharmacological profile: the design and development of...

TPA023 is a GABA(A) alpha2/alpha3 subtype-selective modulator which in preclinical species has anxiolytic-like activity but does not produce sedative-like properties and is without abuse potential. It has good oral bioavailability in rat and dog but not in rhesus monkey (respective oral bioavailability values of 36, 54, and 1%), and in all the three species the half-life after i.v. administration was relatively short (0.6-1.5 h). The plasma concentrations of TPA023 required to produce 50% receptor occupancy were 21-25, 19, and 9 ng/mL in rats, baboons, and humans, respectively. In man, TPA023 has a half-life of around 3-6h when administered as an immediate release formulation, but exposure was more prolonged when it was formulated into a controlled release, gel extrusion module (GEM) tablet. In vivo metabolism was via t-butyl hydroxylation and N-deethylation. A drug-drug interaction study with itraconazole confirmed in vitro metabolic results implicating CYP3A enzymes as the major contributors to in vivo oxidative metabolism. The maximum tolerated doses in healthy, normal volunteers were 2 and 8mg for the immediate-release and GEM formulations, respectively. A post hoc analysis of three separate Phase IIa studies, all of which were halted prematurely, showed that TPA023 reduced scores on the Hamilton Anxiety Scale to a significantly greater extent than placebo. In addition, TPA023 has recently been reported to produce a trend toward improved cognitive performance in a small group of schizophrenia patients. Collectively, these data demonstrate that the alpha2/alpha3-selective partial agonist efficacy of TPA023 translates into a novel pharmacological profile.