LY3130481 - CAS 1610802-47-5
Catalog number: 1610802-47-5
Category: Inhibitor
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LY3130481, a benzothiazol derivative, has been found to be the first AMPA receptor antagonist that could be probably effective in studies of epilepsy. It has just been planed a Phase I trial by Cerecor.
LY3130481; LY-3130481; LY 3130481; CERC-611; CERC611; CERC 611. (S)-6-(1-(1-(5-(2-hydroxyethoxy)pyridin-2-yl)-1H-pyrazol-3-yl)ethyl)benzo[d]thiazol-2(3H)-one
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1.Auxiliary subunits of AMPA receptors: The discovery of a forebrain-selective antagonist, LY3130481/CERC-611.
Kato AS;Witkin JM Biochem Pharmacol. 2018 Jan;147:191-200. doi: 10.1016/j.bcp.2017.09.015. Epub 2017 Oct 5.
Drugs originate from the discovery of compounds, natural or synthetic, that bind to proteins (receptors, enzymes, transporters, etc.), the interaction of which modulates biological cascades that have potential therapeutic benefit. Rational strategies for identifying novel drug therapies are typically based on knowledge of the structure of the target proteins and the design of new chemical entities that modulate these proteins in a beneficial manner. The present review discusses a novel approach to drug discovery based on the identification and characterization of auxiliary proteins, the transmembrane AMPA receptor regulatory proteins (TARPs) that are associated with AMPA receptors. Utilizing these auxiliary proteins in compound screening led to the discovery of the TARP-dependent-AMPA forebrain selective receptor antagonist (TDAA), LY3130481/CERC-611 that is currently in clinical development for epilepsy.
2.Electroencephalographic, cognitive, and neurochemical effects of LY3130481 (CERC-611), a selective antagonist of TARP-γ8-associated AMPA receptors.
Witkin JM;Li J;Gilmour G;Mitchell SN;Carter G;Gleason SD;Seidel WF;Eastwood BJ;McCarthy A;Porter WJ;Reel J;Gardinier KM;Kato AS;Wafford KA Neuropharmacology. 2017 Nov;126:257-270. doi: 10.1016/j.neuropharm.2017.07.028. Epub 2017 Jul 28.
6-[(1S)-1-[1-[5-(2-hydroxyethoxy)-2-pyridyl]pyrazol-3-yl]ethyl]-3H-1,3-benzothiazol-2-one (LY3130481 or CERC-611) is a selective antagonist of AMPA receptors containing transmembrane AMPA receptor regulatory protein (TARP) γ-8. This molecule has been characterized as a potent and efficacious anticonvulsant in an array of acute and chronic epilepsy models in rodents. The present set of experiments was designed to assess the effects of LY3130481 on the electroencephelogram (EEG), cognitive function, and neurochemical outflow. LY3130481 disrupted food-maintained responding in rats and spontaneous alternation in a Y-maze in mice. In rat fear conditioning, LY3130481 caused a deficit in trace (hippocampal-dependent), but not in delay fear conditioning. Although these effects on cognitive performances were observed, the known cognitive-impairing anticonvulsant, topiramate, did not always produce deficits under these assay conditions. LY3130481 produced modest increases in wake times in rats. In addition, LY3130481 was able to attenuate some impairing effects of standard antiepileptic drugs. The motor-impairing effects of the lacosamide were attenuated by LY3130481 as was the decrease in non-rapid-eye movement sleep induced by carbamazepine.
3.Forebrain-selective AMPA-receptor antagonism guided by TARP γ-8 as an antiepileptic mechanism.
Kato AS;Burris KD;Gardinier KM;Gernert DL;Porter WJ;Reel J;Ding C;Tu Y;Schober DA;Lee MR;Heinz BA;Fitch TE;Gleason SD;Catlow JT;Yu H;Fitzjohn SM;Pasqui F;Wang H;Qian Y;Sher E;Zwart R;Wafford KA;Rasmussen K;Ornstein PL;Isaac JT;Nisenbaum ES;Bredt DS;Witkin JM Nat Med. 2016 Dec;22(12):1496-1501. doi: 10.1038/nm.4221. Epub 2016 Nov 7.
Pharmacological manipulation of specific neural circuits to optimize therapeutic index is an unrealized goal in neurology and psychiatry. AMPA receptors are important for excitatory synaptic transmission, and their antagonists are antiepileptic. Although efficacious, AMPA-receptor antagonists, including perampanel (Fycompa), the only approved antagonist for epilepsy, induce dizziness and motor impairment. We hypothesized that blockade of forebrain AMPA receptors without blocking cerebellar AMPA receptors would be antiepileptic and devoid of motor impairment. Taking advantage of an AMPA receptor auxiliary protein, TARP γ-8, which is selectively expressed in the forebrain and modulates the pharmacological properties of AMPA receptors, we discovered that LY3130481 selectively antagonized recombinant and native AMPA receptors containing γ-8, but not γ-2 (cerebellum) or other TARP members. Two amino acid residues unique to γ-8 determined this selectivity. We also observed antagonism of AMPA receptors expressed in hippocampal, but not cerebellar, tissue from an patient with epilepsy. Corresponding to this selective activity, LY3130481 prevented multiple seizure types in rats and mice and without motor side effects.
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