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1.The non-clinical pharmacokinetic profiles of rovatirelin, a novel thyrotropin-releasing hormone (TRH) analogue, were investigated in vivo and in vitro. 2.Rovatirelin orally administered to rats and dogs was rapidly absorbed and bioavailability was estimated to be 7.3 and 41.3%, respectively. The extent of plasma protein binding of rovatirelin in rats, dogs, and humans was low in all species (∼15%). The permeability of rovatirelin from blood to brain (permeability-surface area) ranged from 1.04 ± 0.14 to 1.29 ± 0.28 μL/min/g in rats, and rovatirelin was stable in rat plasma and brain homogenates. 3.The metabolite pattern was qualitatively similar in vitro and in vivo. In animals, rovatirelin aminopentanoic acid (rovatirelin-acid), rovatirelin aminopentanone (rovatirelin-ketone), rovatirelin pyrrolidine (4S)-hydroxy (rovatirelin-OH), (thiazoylalanyl)methylpyrrolidine (TAMP), 3-(4-thiazoyl)-L-alanine (TA), and unknown metabolites were observed. In human hepatocytes, TAMP was mainly formed and no unique human metabolite was observed. 4.The radioactivity from administered [14C]rovatirelin was predominantly excreted in faeces in rats and dogs, and almost all radioactivity was recovered 168 h after administration. Absorption, brain penetration, and stability of rovatirelin in the brain were greater than for taltirelin. 5.Thus, orally administered rovatirelin is a potentially improved treatment for spinocerebellar degeneration compared with taltirelin. [ABSTRACT FROM AUTHOR]

Rovatirelin is a newly synthetized thyrotropin-releasing hormone (TRH) analog. This study aimed to investigate the effect of rovatirelin on motor function using rolling mouse Nagoya (RMN), a mouse model of hereditary ataxia, and compare it with that of taltirelin, which is clinically used to treat spinocerebellar degeneration in Japan. We also examined the effect of rovatirelin on glucose metabolism in various brain regions of RMN using autoradiography (ARG). Rovatirelin (1, 3, 10, and 30 mg/kg) dose-dependently reduced the fall index in RMN, and its effect was more potent than that of taltirelin (3, 10, 30, and 100 mg/kg). No attenuation of the effect was observed by repeated daily administration for 2 weeks. Furthermore, the reduction in the fall index by rovatirelin persisted for 2 weeks after completing treatment. In the ARG study, rovatirelin induced a significantly elevated uptake of glucose in the prefrontal cortex, nucleus accumbens shell, nucleus accumbens core, striatum, anterior cingulate cortex, secondary motor area, pretectal area, ventral tegmental area, black pars compacta, locus coeruleus, nucleus cerebellaris middle nucleus, medial nucleus of the vestibular nerve, fourth/fifth lobule, and third lobule. Furthermore, rovatirelin increased cerebellar mRNA level of brain derived neurotrophic factor. These results suggest that rovatirelin activates the cerebellum and other parts of the central nervous system to improve motor function in spinocerebellar ataxia (SCA) model animals, and its action is more potent than that of taltirelin. Therefore, rovatirelin can be a potential alternative to the traditionally used therapeutics for SCA. [ABSTRACT FROM AUTHOR]