Discovery of 7-arylsulfonyl-1,2,3,4, 4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridines: identification of a potent and selective 5-HT₆ receptor antagonist showing activity in rat social recognition test.
Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited ∼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat social recognition test.
Worldwide Discovery Research, Cephalon, Inc., 145 Brandywine Parkway, West Chester, PA 19380, USA. rtripath@cephalon.com
Rabindranath
R
Tripathy
Robert J
RJ
McHugh
Edward R
ER
Bacon
Joseph M
JM
Salvino
George C
GC
Morton
Lisa D
LD
Aimone
Zeck
Z
Huang
Joanne R
JR
Mathiasen
Amy
A
DiCamillo
Mark J
MJ
Huffman
Beth A
BA
McKenna
Karla
K
Kopec
Lily D
LD
Lu
Jie
J
Qian
Thelma S
TS
Angeles
Thomas
T
Connors
Chrysanthe
C
Spais
Beverly
B
Holskin
Emir
E
Duzic
Hervé
H
Schaffhauser
Gerard C
GC
Rossé
D000818:Animals; D001921:Brain / Q000187:drug effects*; D004285:Dogs; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects; D015394:Molecular Structure; D051381:Rats; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D013237:Stereoisomerism; D013450:Sulfones / Q000737:chemistry* / Q000494:pharmacology*
D006575:Heterocyclic Compounds, 3-Ring; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013450:Sulfones; C097216:serotonin 6 receptor