Himbacine derived thrombin receptor (PAR-1) antagonists: SAR of the pyridine ring.
The structure-activity relationship (SAR) of the vinyl pyridine region of himbacine derived thrombin receptor (PAR-1) antagonists is described. A 2-vinylpyridyl ring substituted with an aryl or a heteroaryl group at the 5-position showed the best overall PAR-1 affinity and pharmacokinetic properties. One of the newly discovered analogs bearing a 5-(3-pyridyl) substituent showed excellent PAR-1 affinity (Ki = 22 nM) and oral activity with reduced ClogP and improved off-target selectivity compared to an earlier development candidate.
Xia
Yan
Y
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA. yan.xia@spcorp.com
Chackalamannil
Samuel
S
Clasby
Martin
M
Doller
Darío
D
Eagen
Keith
K
Greenlee
William J
WJ
Tsai
Hsingan
H
Agans-Fantuzzi
Jacqueline
J
Ahn
Ho-Sam
HS
Boykow
George C
GC
Hsieh
Yunsheng
Y
Lunn
Charles A
CA
Chintala
Madhu
M
D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology; D005663:Furans / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry* / Q000494:pharmacology*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship
D000470:Alkaloids; D000925:Anticoagulants; D005663:Furans; D009281:Naphthalenes; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; C048172:himbacine