Synthesis and SAR of tolylamine 5-HT6 antagonists.
The synthesis and SAR of tolylamines with 5-HT(6) receptor antagonist activity is presented. The amine, core aromatic, peripheral aromatic, and ether linker moieties of HTS hit 1 were modulated and the effect on potency at 5-HT(6) examined. Tolylpiperidine ether 9h was found to possess desirable pharmacokinetic (PK) properties, and was also shown to enhance cognition in the rat novel object recognition paradigm.
Singer
Jamie M
JM
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Wilson
Michael W
MW
Johnson
Paul D
PD
Graham
Shelley R
SR
Cooke
Leonard W
LW
Roof
Robin L
RL
Boxer
Peter A
PA
Gold
Lisa H
LH
Meltzer
Leonard T
LT
Janssen
Ann
A
Roush
Nicole
N
Campbell
Jeffrey E
JE
Su
Ti-Zhi
TZ
Hurst
Susan I
SI
Stoner
Chad L
CL
Schwarz
Jacob B
JB
D000588:Amines / Q000737:chemistry*; D000818:Animals; D002625:Chemistry, Organic / Q000379:methods; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D004987:Ethers / Q000737:chemistry; D020128:Inhibitory Concentration 50; D007700:Kinetics; D008956:Models, Chemical; D051381:Rats; D011985:Receptors, Serotonin / Q000737:chemistry*; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000588:Amines; D004987:Ethers; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; C097216:serotonin 6 receptor