Abstract

In order to provide back-up compounds to support the development of the GABA_A receptor (GABAAR) potentiator, KRM-II-81, three novel analogs were designed: replacement of the pyridinyl with Cl-phenyl (FR-II-60), changing the positions of the N and O atoms in the oxazole ring with addition of an ethyl group (KPP-III-34 and KPP-III-51), or substitution of a Br atom for the ethinyl of KRM-II-81 (KPP-III-34). The compounds bound to brain GABAARs. Intraperitoneal administration of FR-II-60 and KPP-III-34 produced anticonvulsant activity in mice (maximal electroshock (MES)-induced seizures or 6 Hz-induced seizures) whereas KPP-III-51 did not. Although all compounds were orally bioavailable, structural changes reduced the plasma and brain (FR-II-60 and KPP-III-51) exposure relative to KRM-II-81. Oral administration of each compound produced dose-dependent increases in the latency for both clonic and tonic seizures and the lethality induced by pentylenetetrazol (PTZ) in mice. Since KPP-III-34 produced the highest brain AUC exposures, it was selected for further profiling. Oral administration of KPP-III-34 suppressed seizures in corneal-kindled mice, hippocampal paroxysmal discharges in mesial temporal lobe epileptic mice, and PTZ-induced convulsions in rats. Only transient sensorimotor impairment was observed in mice and doses of KPP-III-34 up to 500 mg/kg did not produce impairment in rats. Molecular docking studies demonstrated that all compounds displayed a reduced propensity for binding to α1His102 compared to the sedating compound alprazolam; the bromine-substituted KPP-III-34 achieved the least interaction. Overall, these findings document the oral bioavailability and anticonvulsant efficacy of three novel analogs of KRM-II-81 with reduced sedative effects.

Significance Statement Sedation and tolerance development are obstacles to the development of improved antiepileptic drugs. A new non-sedating compound, KRM-II-81, with reduced propensity for tolerance is currently moving into clinical development. The three backup compounds evaluated in current study were orally bioavailable, produced anticonvulsant effects in rodents, and displayed low cytotoxicity and sensorimotor impairment. An advanced compound, KPP-III-34, demonstrated efficacy in models of pharmacoresistant epilepsy. Molecular docking studies demonstrated a low propensity for compound binding to the α1His102 residue implicated in sedation.