Himbacine derived thrombin receptor (PAR-1) antagonists: structure-activity relationship of the lactone ring.
The structure-activity relationship (SAR) of the lactone ring of himbacine derived thrombin receptor (PAR-1) antagonists (e.g., 2-5) is described. The effect of the lactone carbonyl group on binding to PAR-1 is dependent on the substitution pattern of the pyridine ring. A stereoselective intramolecular Michael addition reaction to the vinyl pyridine group was observed for these pyridine analogs of himbacine in basic conditions at elevated temperature.
Xia
Yan
Y
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. yan.xia@spcorp.com
Chackalamannil
Samuel
S
Chan
Tze-Ming
TM
Czarniecki
Michael
M
Doller
Darío
D
Eagen
Keith
K
Greenlee
William J
WJ
Tsai
Hsingan
H
Wang
Yuguang
Y
Ahn
Ho-Sam
HS
Boykow
George C
GC
McPhail
Andrew T
AT
D000470:Alkaloids / Q000737:chemistry*; D005663:Furans / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D007783:Lactones / Q000737:chemistry*; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D044463:Receptor, PAR-1 / Q000378:metabolism; D013329:Structure-Activity Relationship; D010975:Platelet Aggregation Inhibitors
D000470:Alkaloids; D005663:Furans; D007783:Lactones; D009281:Naphthalenes; D010880:Piperidines; D044463:Receptor, PAR-1; C048172:himbacine; D010975:Platelet Aggregation Inhibitors