RT Journal Article
SR Electronic
T1 <strong>Structural analogs of the GABAkine </strong><strong>(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[</strong><strong><em>f</em></strong><strong>]imidazole[1,5-α</strong><strong>]</strong><strong>[1,4]diazepin-3-yl) oxazole)</strong> (<strong>KRM-II-81) are orally bioavailable anticonvulsants without sedation<sup>1</sup></strong>
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP JPET-AR-2022-001362
DO 10.1124/jpet.122.001362
A1 Kamal P Pandey
A1 Branka Divović
A1 Farjana Rashid
A1 Lalit K Golani
A1 Rok Cerne
A1 Nicolas M Zahn
A1 Michelle J Meyer
A1 Alexander (Leggy) Arnold
A1 Dishary Sharmin
A1 Md Yeunus Mian
A1 Jodi L Smith
A1 Xingjie Ping
A1 Xiaoming Jin
A1 Arnold Lippa
A1 V. V. N. Phani Babu Tiruveedhula
A1 James M. Cook
A1 Miroslav Savic
A1 Jeffrey M. Witkin
YR 2023
UL http://jpet.aspetjournals.org/content/early/2023/02/03/jpet.122.001362.abstract
AB In order to provide back-up compounds to support the development of the GABAA 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.