Tricyclic azepine derivatives as selective brain penetrant 5-HT6 receptor antagonists.
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
Trani
Giancarlo
G
Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Third Avenue, Harlow, Essex CM19 5AW, UK. Giancarlo.Z.Trani@gsk.com
Baddeley
Stuart M
SM
Briggs
Michael A
MA
Chuang
Tsu T
TT
Deeks
Nigel J
NJ
Johnson
Christopher N
CN
Khazragi
Abir A
AA
Mead
Tania L
TL
Medhurst
Andrew D
AD
Milner
Peter H
PH
Quinn
Leann P
LP
Ray
Alison M
AM
Rivers
Dean A
DA
Stean
Tania O
TO
Stemp
Geoffrey
G
Trail
Brenda K
BK
Witty
David R
DR
D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D001812:Blood-Brain Barrier / Q000187:drug effects; D001921:Brain / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D051544:Cytochrome P-450 CYP3A; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D008861:Microsomes / Q000187:drug effects; D008956:Models, Chemical; D008968:Molecular Conformation; D020033:Protein Isoforms; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology
D000929:Antidepressive Agents, Tricyclic; D020033:Protein Isoforms; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; C097216:serotonin 6 receptor; D003577:Cytochrome P-450 Enzyme System; C465260:Cyp3a2 protein, rat; D051544:Cytochrome P-450 CYP3A