Pharmacological Characterization of RO5461861, a Potent and Selective PDE10A Inhibitor


Schaffhauser, H., Prinssen, E. P., Honer, M., Ballard, T. M., Wallace, T. L., Peters, J.-U., . . . Flohr, A. (2014, 15-19 November). Pharmacological characterization of RO5461861, a potent and selective PDE10A inhibitor. Paper presented at Neuroscience 2014, Washington, DC.


Inhibition of PDE10A is considered a promising approach for the treatment of multiple symptomatic domains of schizophrenia and Huntington’s Disease (HD). Here we describe the characterization of a new class of potent PDE10A inhibitors exemplified by 4-(Azetidine-1 -carbonyl)-2-methyl-2-H-pyrazole-3-carboxylic acid (2-phenylimidazo[1,2-a]pyrimidin-7-yl)-amide (RO5461861) in vitro as well as in behavioral tests relevant to NMDA-R hypofunction and working memory. RO5461861 inhibited the PDE10A enzyme with nanomolar potency, was selective against the other members of the phosphodiesterase family and had good pharmacokinetic properties in different preclinical species. The binding of [3H]RO5461861 was characterized in both rat striatal membranes as well as in brain sections. Blocking and displacement experiments were performed using reported selective PDE10A inhibitors. [3H]RO5461861 binding was saturable in the rat striatum and demonstrated high-affinity binding to a single site. The calculated Kd and Bmax values were 1.35 ± 0.35 nM and 3.99 ± 0.26 pmol mg-1 of protein respectively. In sagittal sections of rat brain, a high density of specific binding was observed in the striatum, substantia nigra, olfactory tubercle and globus pallidus. Less binding was observed in the hippocampus, in the different layers of the cortex and cerebellum. Oral administration of RO5461861 dose dependently reversed ketamine-induced hyperlocomotion in mice and MK801-induced hyperlocomotion in rats with ED50s of 0.7 and 0.87 mg/kg respectively. Catalepsy in rats was observed only at higher doses (minimally effective dose [MED] = 3 mg/kg). RO5461861 increased accuracy in the delayed match to sample (DMTS) in Cynomolgus macaques at a dose (3 mg/kg, oral) which did not produce extrapyramidal symptoms. Collectively, the present data demonstrate that RO5461861 has utility in investigating the potential of PDE10A inhibition for the treatment of schizophrenia or HD and highlight the value of [3H]RO5461861 in characterizing new chemical entities.

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