Andrew Pike

RAT PHARMACOKINETICS AND PHARMACODYNAMICS OF A SUSTAINED RELEASE FORMULATION OF THE GABAA α5-SELECTIVE COMPOUND L-655,708

The pharmacokinetic and pharmacodynamic (i.e., receptor occupancy) properties of L-655,708, a compound with selectivity for α5-over α1-, α2-, and α3-containing GABAA receptors, were examined in rats with the aim of developing a formulation that would give sustained (up to 6 h) and selective occupancy of α5-containing GABAA receptors suitable for behavioral studies. Standard rat pharmacokinetic analyses showed that L-655,708 has a relatively short half-life with kinetics in the brain mirroring those in the plasma. In vivo binding experiments showed that plasma concentrations of around 100 ng/ml gave relatively selective in vivo occupancy of rat brain α5-versus α1-, α2-, and α3-containing GABAA receptors. Therefore, this plasma concentration was chosen as a target to achieve relatively selective occupancy of α5-containing receptors using s.c. implantations of L-655,708 (0.4, 1.5, or 2.0 mg) formulated into tablets of various size (20 or 60 mg) containing different amounts of L-655,708 and combinations of low and high viscosity hydroxypropyl methylcellulose (LV- and HV-HPMC). The optimum formulation, 1.5 mg of L-655,708 compressed into a 60-mg tablet with 100% HV-HPMC, resulted in relatively constant plasma concentrations being maintained for at least 6 h with very little difference between Cmax concentrations (125–150 ng/ml) and plateau concentrations (100–125 ng/ml). In vivo binding experiments confirmed the selective occupancy of rat brain α5-over α1-, α2-, and α3-containing GABAA receptors.

Identification of an Orally Bioavailable, Potent, and Selective Inhibitor of GlyT1.

Amalgamation of the structure-activity relationship of two series of GlyT1 inhibitors developed at Merck led to the discovery of a clinical candidate, compound 16 (DCCCyB), which demonstrated excellent in vivo occupancy of GlyT1 transporters in rhesus monkey as determined by displacement of a PET tracer ligand.