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.
Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA.
Jamie M
JM
Singer
Michael W
MW
Wilson
Paul D
PD
Johnson
Shelley R
SR
Graham
Leonard W
LW
Cooke
Robin L
RL
Roof
Peter A
PA
Boxer
Lisa H
LH
Gold
Leonard T
LT
Meltzer
Ann
A
Janssen
Nicole
N
Roush
Jeffrey E
JE
Campbell
Ti-Zhi
TZ
Su
Susan I
SI
Hurst
Chad L
CL
Stoner
Jacob B
JB
Schwarz
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