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  • Reports of hyperlocomotion after administration

    2022-06-23

    Reports of hyperlocomotion after administration of ALX-5407 [27] coupled with the lack of hyperlocomotion after administration of SSR504734, a non-sarcosine, long-residence time, competitive inhibitor [19], suggested that the GlyT1 inhibitor chemotype may impact OP. Furthermore, a compound with a competitive mode of inhibition may be expected to display reduced toxicity since inhibition can be overcome as substrate concentration rises. Specifically, reversible, non-sarcosine-derived inhibitors, such as SSR504734, may be desirable. However, off-target activity at the κ-opiate receptor was observed during selectivity profiling of SSR504734 (data not shown), and this compound was not investigated further. In the present study, OP was induced by (S)-13h, a selective, competitive GlyT1 inhibitor that lacks a sarcosine moiety. (S)-13h produced peak levels of OP comparable to the sarcosine-derived, mixed noncompetitive inhibitor ALX-5407. The duration of action for (S)-13h was shorter, consistent with the reversible nature of its inhibition of GlyT1 and pharmacokinetic profile. This comparison suggests that neither the lack of a sarcosine moiety nor a competitive mode of inhibition is sufficient to ameliorate OP. In the present study, OP was induced by GlyT1 inhibitors independently of compound mode of inhibition and chemotype (Table 2) [cf. 28]. Other parameters including potency and compound concentration in SAR131675 (data not shown) also did not afford improvement in OP. Because the two compounds in this study that did not induce OP, Roche-7 and sarcosine, are the two less potent compounds, one might think that compound potency against GlyT1 induces OP. However, a proprietary GlyT1 inhibitor with weaker potency than Roche-7 was tested, and this compound also produced OP in our hands. Thus even weak GlyT1 inhibitors are capable of producing OP. In addition, the pharmacokinetic profile of (S)-13h indicated that it had the lowest brain concentration and highest clearance of the compounds tested, suggesting that SAR131675 these parameters did not correlate with improved behavior. Sarcosine and Roche-7, compounds with short residence times, produced only mild hypoactivity, similar to the effect of d-serine, a GlyB site agonist. Thus, of the four compounds tested in the present study, the key mechanistic determinant for amelioration of OP was target residence time. Identification of a set of GlyT1 inhibitors with similar chemotype and mode of inhibition but with a range of residence times would lend additional support to this hypothesis. There was greater than 1000-fold difference in potency between sarcosine and Roche-7, demonstrating that potency did not correlate with residence time for GlyT1 inhibitors and that a potent GlyT1 inhibitor can be efficacious without inducing OP. There is a growing appreciation that target residence time, or the dissociative half-life of the compound–target complex, is an important mechanistic parameter with significant implications for determining both in vivo efficacy and adverse effect [50], [51]. In particular, target residence time appears to be a key determinant, along with pharmacokinetics, of the in vivo duration of action of a compound. Based on the results of the present study, compounds such as ALX-5407 and (S)-13h with relatively long target residence times resulted in OP at the same doses that produced efficacy in the PPI model. However, sarcosine and Roche-7, compounds with relatively short target residence times did not produce OP and, in the case of Roche-7, exhibited at least a 10-fold improvement in therapeutic index. Theoretically, the more rapid dissociation of the inhibitor from the transporter may allow glycine to more effectively compete for transport. This may allow for better regulation and maintenance of glycine concentrations in an efficacious range without significantly impacting GlyA receptors. The reason a short residence time GlyT1 inhibitor may differentially impact the two types of synapses, i.e. glutamatergic and glycinergic, is not known. Speculatively, the glycine load may be greater at the glycine receptor after vesicular release than it is at the NMDA receptor, where the glycine concentration is that found in the extracellular milieu. Therefore, it may be possible to mitigate the adverse effects of GlyT1 inhibitors and maintain efficacy by developing a drug-like compound that possesses a short (<10min) target half-life. Recently, Roche reported the outcome from a Phase II trial with a proprietary compound, RG1678, which was given as an add-on treatment to stably medicated patients with schizophrenia [14] (www.roche.com). RG1678 improved negative symptoms and was well tolerated in these patients. While the residence time of this compound has not been reported, it would be of interest to determine this parameter in light of the short residence time of Roche-7. Future studies with additional compounds possessing a profile similar to Roche-7 and clinical safety studies will be required to fully determine if GlyT1 is a viable antipsychotic target.