title: High-affinity thrombin receptor (PAR-1) ligands: a new generation of indole-based peptide mimetic antagonists with a basic amine at the C-terminus.
abstract: A new generation of indole-based peptide mimetics, bearing a basic amine at the C-terminus, was developed by the agency of two complementary, multistep, trityl resin-based approaches. Thus, we obtained several high-affinity thrombin receptor (PAR-1) ligands, such as 32 and 34. Compounds 32 and 34 were found to bind to PAR-1 with excellent affinity (IC(50)=25 and 35 nM, respectively) and to effectively block platelet aggregation induced by SFLLRN-NH(2) (TRAP-6) and alpha-thrombin.
authors.affiliation: Drug Discovery, Johnson & Johnson Pharmaceutical Research & Development, 19477-0776, Spring House, PA, USA. hzhang@prdus.jnj.com
authors.forename: Han Cheng
authors.initials: HC
authors.lastname: Zhang
authors.forename: Kimberly B
authors.initials: KB
authors.lastname: White
authors.forename: David F
authors.initials: DF
authors.lastname: McComsey
authors.forename: Michael F
authors.initials: MF
authors.lastname: Addo
authors.forename: Patricia
authors.initials: P
authors.lastname: Andrade-Gordon
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Derian
authors.forename: Donna
authors.initials: D
authors.lastname: Oksenberg
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
mesh_terms: D000588:Amines / Q000737:chemistry; D006490:Hemostatics / Q000037:antagonists & inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007191:Indazoles / Q000737:chemistry; D007211:Indoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D008024:Ligands; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000037:antagonists & inhibitors / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D018179:Receptors, Thrombin / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry
chemical_list: D000588:Amines; D006490:Hemostatics; D007191:Indazoles; D007211:Indoles; D008024:Ligands; D010446:Peptide Fragments; C435606:RWJ-56110; D018179:Receptors, Thrombin; C082835:thrombin receptor peptide (42-47); D014508:Urea; D013917:Thrombin