Ased on these results, the possible for CNS toxicity was examined for phenyl mexiletine analogs 1922. No apparent toxicity or seizures had been observed for racemic 1922 administered at 30 or 100 mg/kg in mice. All mice examined (4 animals) administered 192 at 30 or one hundred mg/kg did not show any toxicity (i.e., seizures or deaths). Each enantiomers of 22 showed no CNS toxicity, whereas 21 showed detectable toxicity (100 mg/kg) (Table 5). Though not a complete dose-escalation study, nevertheless phenylmexiletine was metabolized below standard circumstances (Tables three and four). Using the exception of compound 14 in mouse S-9, compared to mexiletine, deuterated compounds 13, 15, and 16 were metabolized to a less degree as judged by HPLC (Table 4). As discussed above, deuterated phenyl mexiletine analogs had been synthesized and tested for metabolic stability in hepatic preparations or hugely purified enzymes to identify if deuteration would decrease metabolism in comparison with mexiletine. When compared with mexiletine, information of Table 4, below, showed that deuterated analogs 13, 14, 15, and 16 were more metabolically steady. One example is, compounds 13, 14, 15, and 16 have been 8.5-, 4.8-, 6.7-, and 22-fold, respectively, much less metabolized by human FMO1 compared to mexiletine. Compounds 13, 14, 15, and 16 were 2.7-, 3-, 9.9-, and 9.9-fold, respectively, much less metabolized by human CYP3A4 compared to mexiletine. In general, when compared with mexiletine, the impact in the deuterium isotope was very apparent for deuterated compounds 136 in comparison with nondeuterated mexiletine. The effect of such a pronounced impact of deuterium on metabolic stability could translate to a large impact on pharmacological response, in vivo metabolism, a decrease in clearance, higher bioavailability, and greater efficacy. This was examined for selected compounds in safety and pharmacokinetic research below.TA B L E five Effectof(R)- or (S)-Mexiletine or Mexiletine analog treatment on behavior in miceCompound (R)-Mexiletine (S)-Mexiletine (R)-Mexiletine (S)-Mexiletine (R)-Mexiletine (S)-Mexiletine (R)-21 (S)-21 (R)-22 (S)-a bDosea (mg/ kg) 30 30 one hundred one hundred 200 200 one hundred one hundred 100Seizures immobilizationb/dosed 0/4 4/4c 3/4 7/7 1/4 3/4d 4/4e 3/4e 0/4 0/3.4 | In vivo studies three.four.1 | BehavioralstudiesMexiletine triggered seizures at elevated doses in mice (Table 5). In our hands, after P2X7 Receptor Inhibitor manufacturer administration of 30 mg/kg (R)-mexiletine, 0/4 mice had seizures or tremors. In contrast, immediately after a dose of 30 mg/kg (S)mexiletine, 4/4 mice had seizures. Immediately after administration of 100 mg/ kg (R)-mexiletine, mice had seizures but right after administration of one hundred mg of (S)-mexiletine, 7/7 mice had seizures. Just after administration of 200 mg/kg (R)-mexiletine to mice, 1/4 mice had seizures. In contrast, mice administered (S)-mexiletine at 200 mg/kg showedMexiletines have been administered in saline by i.p. injection.Cumulative behavior in the course of the first 20 min following dosing. Following 2 h, surviving animals were largely recovered. Significantly distinct from (R)-mexiletine, p = .05, Fishers precise mGluR5 Modulator Storage & Stability probability test. One animal died in the very first 20 min following dosing. No seizures, only immobilization.cd eTA B L E 4 MetabolicstabilityofunlabeledmexiletineanddeuteratedanalogsofphenylmexiletineCompound Mexiletine 13 14 15aMouse liver S-9 (rate metabolized)a 0.43 0.01 ND 1.1 0.09 ND NDcc cHuman FMO1 (price metabolized)a 14.88 0.15 1.77 0.12 3.11 0.05 two.22 0.04 0.67 0.Human FMO3 (price metabolized)a NDc 1.33 0.11 2.88 0.09 0.11 0.01 1.55 0.Human CYP3A4 (rate metabolized)b 7.four 0.12 2.7.
