1-Sulfonylindazoles as potent and selective 5-HT6 ligands.
As part of our continuing efforts to identify therapeutics for CNS diseases, such as schizophrenia and Alzheimer's disease (AD), we have been focused on the 5-HT(6) receptor in an attempt to identify ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of 1-sulfonylindazole derivatives as potent and selective 5-HT(6) antagonists. The synthesis and SAR of this class of compounds are reported. Several potent compounds in both binding and cyclase functional assays also display good selectivity, microsomal stability, solubility, and brain penetration as well as low cytochrome P450 inhibition. One compound exemplified in this series showed 24% oral bioavailability and in vivo efficacy in a NOR cognition model at 10mg/kg following an oral administration in rats.
Liu
Kevin G
KG
Chemical Sciences, Wyeth Research, CN 8000, Princeton, NJ 08543, USA.
Lo
Jennifer R
JR
Comery
Thomas A
TA
Zhang
Guo Ming
GM
Zhang
Jean Y
JY
Kowal
Dianne M
DM
Smith
Deborah L
DL
Di
Li
L
Kerns
Edward H
EH
Schechter
Lee E
LE
Robichaud
Albert J
AJ
D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D002493:Central Nervous System Diseases / Q000188:drug therapy; D003072:Cognition Disorders / Q000188:drug therapy; D015195:Drug Design; D006801:Humans; D007191:Indazoles / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008024:Ligands; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000737:chemistry*
D007191:Indazoles; D008024:Ligands; D011985:Receptors, Serotonin; C097216:serotonin 6 receptor