Heterocycle-peptide hybrid compounds. Aminotriazole-containing agonists of the thrombin receptor (PAR-1).
The thrombin receptor PAR-1 is activated by alpha-thrombin to stimulate cells, including platelets, through the tethered-ligand sequence SFLLRN. We have discovered a novel series of heterocycle-peptide hybrids comprised of a tripeptide segment, such as Cha-Arg-Phe, and an N-terminal heterocyclic group, many of which behave as full PAR-1 agonists. Certain compounds with an aminotriazole group, such as 4 and 16, are nearly as potent as SFLLRN-NH2 in inducing platelet aggregation. Also, some arylethenoyl "N-capped" compounds, such as 52 and 57, exhibit mixed PAR-1 agonist-antagonist activity.
McComsey
D F
DF
Drug Discovery, The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA 19477, USA.
Hawkins
M J
MJ
Andrade-Gordon
P
P
Addo
M F
MF
Oksenberg
D
D
Maryanoff
B E
BE
D002460:Cell Line; D006571:Heterocyclic Compounds / Q000737:chemistry*; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin / Q000819:agonists* / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D014230:Triazoles / Q000737:chemistry*
D006571:Heterocyclic Compounds; D009842:Oligopeptides; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D014230:Triazoles