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Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists |
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| Authors: | Ahmed Mahmood Briggs Michael A Bromidge Steven M Buck Tania Campbell Lorraine Deeks Nigel J Garner Ashley Gordon Laurie Hamprecht Dieter W Holland Vicky Johnson Christopher N Medhurst Andrew D Mitchell Darren J Moss Stephen F Powles Jenifer Seal Jon T Stean Tania O Stemp Geoffrey Thompson Mervyn Trail Brenda Upton Neil Winborn Kim Witty David R |
| Affiliation: | Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. |
| Abstract: |  Starting from the potent and selective but poorly brain penetrant 5-HT6 receptor antagonist SB-271046, a successful strategy for improving brain penetration was adopted involving conformational constraint with concomitant reduction in hydrogen bond count. This provided a series of bicyclic heteroarylpiperazines with high 5-HT6 receptor affinity. 5-Chloroindole 699929 combined high 5-HT6 receptor affinity with excellent brain penetration and also had good oral bioavailability in both rat and dog. |
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