Metabolism, pharmacokinetics, and anticonvulsant activity of a deuterated analog of the α2/3‐selective GABAkine KRM‐II‐81

Abstract

The imidazodiazepine, (5‐(8‐ethynyl‐6‐(pyridin‐2‐yl)‐4H‐benzo [f]imidazole[1,5‐α][1,4]diazepin‐3‐yl) oxazole or KRM‐II‐81) is a new α2/3‐selective GABAkine (gamma aminobutyric acid A receptor potentiator) with anticonvulsant, anxiolytic, and antinociceptive activity in preclinical models. Reducing metabolism was utilized as a means of potentially extending the half‐life of KRM‐II‐81. In vitro and in vivo studies were conducted to evaluate metabolic liabilities. Incubation of KRM‐II‐81 in hepatocytes revealed sites of potential metabolism on the oxazole and the diazepine rings. These sites were targeted in the design of a deuterated analog (D5‐KRM‐II‐81) that could be evaluated as a potentially longer‐acting analog. In contrast to computer predictions, peak plasma concentrations of D5‐KRM‐II‐81 in rats were not significantly greater than those produced by KRM‐II‐81 after oral administration. Furthermore, brain disposition of KRM‐II‐81 was higher than that of D5‐KRM‐II‐81. The half‐life of the two compounds in either plasma or brain did not statistically differ from one another but the tmax for D5‐KRM‐II‐81 occurred slightly earlier than for KRM‐II‐81. Non‐metabolic considerations might be relevant to the lack of increases in exposure by D5‐KRM‐II‐81. Alternative sites of metabolism on KRM‐II‐81, not targeted by the current deuteration process, are also possible. Despite its lack of augmented exposure, D5‐KRM‐II‐81, like KRM‐II‐81, significantly prevented seizures induced by pentylenetetrazol when given orally. The present findings introduce a new orally active anticonvulsant GABAkine, D5‐KRM‐II‐81.

Comparative anticonvulsant activity of the GABAkine KRM‐II‐81 and a deuterated analog

“… a Data are expressed as the number of mice protected (not showing clonus, tonus or lethality)/number of mice tested. The data on these compounds at 120 min is reprinted from Golani et al (2022) with permission of the publisher.…”

“…Although deuteration is one method commonly used to increase compound half‐life (Clarke et al, 2002; F. Schneider et al, 2006; N. Schneider et al, 2020), the sites deuterated in D5‐KRM‐II‐81 (Golani et al, 2022) did not result in increased compound half‐life. Incubation in human microsomes showed no significant changes in t ½ for D5‐KRM‐II‐81 (1227 min) compared to the parent (1495 min) (Golani et al, 2022). Oral exposure studies in rats also did not demonstrate increases in plasma or brain exposure with D5‐KRM‐II‐81.…”

“…against PTZ was unexpected given the lack of statistically significant differences in the plasma or brain half‐lives of the two compounds (Golani et al, 2022). However, it is critical to recognize that the oral exposure data collected in Golani et al (2022) was in rats and the anticonvulsant findings in the present study were derived from mouse studies. A longer oral exposure of D5‐KRM‐II‐81 in mice could be associated with the increased anticonvulsant activity, but at present, there are no mouse data to inform this possibility.…”

“…D5‐KRM‐II‐81 could serve as a structural backup molecule for KRM‐II‐81 as it proceeds into development. Although deuteration did not remarkably alter the half‐life of KRM‐II‐81 in plasma or brain (Golani et al, 2022), in vivo comparisons of duration of action have not been reported.…”

Key Characteristics and Development of Psychoceuticals: A Review

“…Various studies have demonstrated improvement in humans after being exposed to these drugs. Some of the medications that have been shown to decrease depression and anxiety are LSD [ 52 ], peyote [ 58 ], ketamine [ 67 ], arketamine [ 24 , 63 ], N, N-dimethyltryptamine [ 11 ], psilocybin [ 64 ], and deuterated etifoxine [ 59 , 60 ]. Administration of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) has reduced suicidal ideations, planning, and attempts [ 53 , 54 ].…”