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GPCR/G ProteinNeuronal Signaling-

GSK163090???????????????????????????5-HT1A/B/D???????????????,?????????HT1A/B/D????????????D2/D3??????, pKi?????????9.4/8.5/9.7???6.3/6.7???

5-HT ReceptorDopamine Receptor

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生物活性

Description

GSK163090 is a potent, selective, and orally active 5-HT1A/B/D receptor antagonist with pKi of  9.4/8.5/9.7, and 6.3/6.7 for 5-HT1A/B/D, and dopamine D2/D3, respectively.IC50 value: 9.4/8.5/9.7 (pKi) [1]Target: 5-HT in vitro: GSK163090 demonstrates clear dose-dependent inhibition of the 8-OH-DPAT-induced hyperlocomotor activity (hLMA), with ED50 values ranging from 0.03 to 1 mg/kg. GSK163090 was devoid of agonist activity at R1 receptors, but rather it demonstrated amoderate functional antagonismof the phenylephrineinduced contraction of rabbit aorta (pIC50=6.9). [1]in vivo: Fromamong these analogues, the cyclic urea derivative, GSK163090, emerged due to its low hERG affinity and excellent in vitro DMPK profile. The superior quality of GSK163090 was further highlighted by its commendable in vivo pharmacokineticprofile in rat and its outstanding activity in the 5-HT1A PD model, where 50% efficacy was achieved at a blood concentration of 3 ng/mL. On the basis of these results and its promising preclinical developability profile, GSK163090 was selected as an appropriate development candidate for progression toward clinical proof-of-concept studies. [1]

Clinical Trial

NCT00559299

GlaxoSmithKline

Depressive Disorder, Major-Major Depressive Disorder (MDD)

November 2007

Phase 1

NCT00435695

GlaxoSmithKline

Healthy Subjects-Depressive Disorder and Anxiety Disorders

November 2006

Phase 1

NCT00536679

GlaxoSmithKline

Depression-Anxiety Disorder

September 2007

Phase 1

NCT00896363

GlaxoSmithKline

Depressive Disorder

April 1, 2009

Phase 2

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References

[1].Leslie CP, et al. Discovery of 1-(3-{2-[4-(2-methyl-5-quinolinyl)-1-piperazinyl]ethyl}phenyl)-2-imidazolidinone (GSK163090), a Potent, selective, and orally active 5-HT1A/B/D receptor antagonist. J Med Chem. 2010 Dec 9;53(23):8228-8240.