Lu AE58054

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GPCR/G ProteinNeuronal Signaling-

Lu AE58054???5-HT6????????????????????????????????????????????????????????????Ki???0.83 nM???

5-HT Receptor

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生物活性

Description

Lu AE58054 is an in-vitro potency and selectivity, in-vivo binding affinity and effect of the 5-HT(6)R antagonist with a Ki value of 0.83 nM.IC50 Value: 0.83 nm[1]Target: 5-HT(6)Rin vitro: Lu AE58054 displayed high affinity to the human 5-HT(6) receptor (5-HT(6)R) with a Ki of 0.83 nm. In a 5-HT(6) GTPgammaS efficacy assay Lu AE58054 showed no agonist activity, but demonstrated potent inhibition of 5-HT-mediated activation. Besides medium affinity to adrenergic alpha(1A)- and alpha(1B)-adrenoreceptors, Lu AE58054 demonstrated >50-fold selectivity for more than 70 targets examined[1].in vivo: Orally administered Lu AE58054 potently inhibited striatal in-vivo binding of the 5-HT(6) antagonist radioligand [(3)H]Lu AE60157, with an ED(50) of 2.7 mg/kg. Steady-state modelling of an acute pharmacokinetic/5-HT(6)R occupancy time-course experiment indicated a plasma EC(50) value of 20 ng/ml. Administration of Lu AE58054 in a dose range (5-20 mg/kg p.o.) leading to above 65% striatal 5-HT(6)R binding occupancy in vivo, reversed cognitive impairment in a rat novel object recognition task induced after subchronic treatment for 7 d with phencyclidine (PCP 2 mg/kg b.i.d., i.p. for 7 d, followed by 7 d drug free). The results indicate that Lu AE58054 is a selective antagonist of 5-HT(6)Rs with good oral bioavailability and robust efficacy in a rat model of cognitive impairment in schizophrenia[1].Clinical trial: Lu-AE58054 Added to Donepezil for the Treatment for Moderate Alzheimer's Disease. Phage2

Clinical Trial

NCT02415907

H. Lundbeck A/S

Healthy

April 2015

Phase 1

NCT02371707

H. Lundbeck A/S

Healthy

March 2015

Phase 1

NCT02079246

H. Lundbeck A/S

Alzheimer's Disease

April 2014

Phase 3

NCT02340195

H. Lundbeck A/S

Alzheimer Disease

January 2015

Phase 1

NCT02894515

H. Lundbeck A/S

Bioequivalence

September 2016

Phase 1

NCT02436486

H. Lundbeck A/S

Healthy Volunteers

May 2015

Phase 1

NCT02019394

H. Lundbeck A/S

Healthy

December 2013

Phase 1

NCT02122692

H. Lundbeck A/S

Healthy Volunteers

March 2014

Phase 1

NCT02231450

H. Lundbeck A/S

Heptic Impairment

July 2014

Phase 1

NCT02006654

H. Lundbeck A/S-Otsuka Pharmaceutical Co., Ltd.

Alzheimer's Disease

March 2014

Phase 3

NCT02006641

H. Lundbeck A/S-Otsuka Pharmaceutical Co., Ltd.

Alzheimer's Disease

February 2014

Phase 3

NCT01955161

H. Lundbeck A/S-Otsuka Pharmaceutical Co., Ltd.

Alzheimer's Disease

October 2013

Phase 3

NCT00810667

H. Lundbeck A/S

Schizophrenia-Cognition

November 2008

Phase 2

NCT01019421

H. Lundbeck A/S

Alzheimer's Disease

December 2009

Phase 2

NCT01975779

H. Lundbeck A/S

Healthy

July 2013

Phase 1

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References

[1].Arnt J, Bang-Andersen B, Grayson B, Lu AE58054, a 5-HT6 antagonist, reverses cognitive impairment induced by subchronic phencyclidine in a novel object recognition test in rats. Int J Neuropsychopharmacol. 2010 Sep;13(8):1021-33.

[2].Witten L, Bang-Andersen B, Nielsen SM, Characterization of [?H]Lu AE60157 ([?H]8-(4-methylpiperazin-1-yl)-3-phenylsulfonylquinoline) binding to 5-hydroxytryptamine? (5-HT?) receptors in vivo.Eur J Pharmacol. 2012 Feb 15;676(1-3):6-11.