Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists

Mahmood Ahmed; Michael A Briggs; Steven M Bromidge; Tania Buck; Lorraine Campbell; Nigel J Deeks; Ashley Garner; Laurie Gordon; Dieter W Hamprecht; Vicky Holland; Christopher N Johnson; Andrew D Medhurst; Darren J Mitchell; Stephen F Moss; Jenifer Powles; Jon T Seal; Tania O Stean; Geoffrey Stemp; Mervyn Thompson; Brenda Trail; Neil Upton; Kim Winborn; David R Witty

doi:10.1016/j.bmcl.2005.06.107

Bicyclic heteroarylpiperazines as selective brain penetrant 5-HT6 receptor antagonists

Bioorg Med Chem Lett. 2005 Nov 1;15(21):4867-71. doi: 10.1016/j.bmcl.2005.06.107.

Affiliation

¹ Neurology and GI Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK.

PMID: 16143522
DOI: 10.1016/j.bmcl.2005.06.107

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.

MeSH terms

Administration, Oral
Animals
Biological Availability
Blood-Brain Barrier
Brain / metabolism*
Dogs
Molecular Conformation
Permeability
Piperazines / chemical synthesis*
Piperazines / pharmacokinetics
Piperazines / pharmacology
Rats
Receptors, Serotonin / drug effects*
Serotonin Antagonists / chemical synthesis*
Serotonin Antagonists / pharmacokinetics*
Serotonin Antagonists / pharmacology
Structure-Activity Relationship

Substances

Piperazines
Receptors, Serotonin
Serotonin Antagonists
serotonin 6 receptor