Structural Analogs of the GABAkine KRM-II-81 Are Orally Bioavailable Anticonvulsants without Sedation.

Autor:	Pandey KP; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.); kppandey@uwm.edu witkinconsult@gmail.com.; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.); kppandey@uwm.edu witkinconsult@gmail.com.; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.); kppandey@uwm.edu witkinconsult@gmail.com.; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.); kppandey@uwm.edu witkinconsult@gmail.com.; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.) kppandey@uwm.edu witkinconsult@gmail.com., Divović B; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Rashid F; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Golani LK; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Cerne R; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Zahn NM; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Meyer MJ; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Arnold LA; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Sharmin D; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Mian MY; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Smith JL; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Ping X; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Jin X; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Lippa A; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Tiruveedhula VVNPB; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Cook JM; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Savić MM; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.).; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.).; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.).; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.).; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.)., Witkin JM; Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin (K.P.P., F.R., L.K.G., N.M.Z., M.J.M., L.A.A., D.S., M.Y.M., V.V.N.P.B.T., J.M.C., J.M.W.); kppandey@uwm.edu witkinconsult@gmail.com.; Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia (B.D., M.M.S.); kppandey@uwm.edu witkinconsult@gmail.com.; Laboratory of Antiepileptic Drug Discovery, St. Vincent's Hospital, Indianapolis, Indiana (R.C., J.L.S., J.M.W.); kppandey@uwm.edu witkinconsult@gmail.com.; Department of Anatomy and Cell BiologyIndiana University/Purdue University, Indianapolis, Indiana (R.C., X.P., X.J.); kppandey@uwm.edu witkinconsult@gmail.com.; Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia (R.C.); and RespireRx Pharmaceuticals Inc., Glen Rock, New Jersey (A.L., J.M.C., J.M.W.) kppandey@uwm.edu witkinconsult@gmail.com.
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2023 Apr; Vol. 385 (1), pp. 50-61. Date of Electronic Publication: 2023 Feb 06.
DOI:	10.1124/jpet.122.001362
Abstrakt:	To provide back-up compounds to support the development of the GABA A receptor (GABAAR) potentiator KRM-II-81, three novel analogs were designed: replacing the pyridinyl with 2'-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 substituting a Br atom for the ethynyl 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) exposures 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 area under the curve (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 α 1His102 compared with 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: A new non-sedating compound, KRM-II-81, with reduced propensity for tolerance is moving into clinical development. Three new analogs were orally bioavailable, produced anticonvulsant effects in rodents, and displayed low sensorimotor impairment. KPP-III-34 demonstrated efficacy in models of pharmacoresistant epilepsy. Docking studies demonstrated a low propensity for compound binding to the α1His102 residue implicated in sedation. Thus, three additional structures have been added to the list of non-sedating imidazodiazepine anticonvulsants that could serve as backups in the clinical development of KRM-II-81. (Copyright © 2023 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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