title: Design, synthesis and biological evaluation of non-peptide PAR1 thrombin receptor antagonists based on small bifunctional templates: arginine and phenylalanine side chain groups are keys for receptor activity.
abstract: In the present study, we report the synthesis and biological evaluation of a series of new non-peptide PAR(1) mimetic receptor antagonists, based on conformational analysis of the S(42)FLLR(46) tethered ligand (TL) sequence of PAR(1). These compounds incorporate the key pharmacophore groups in the TL sequence, guanidyl, amino and phenyl, which are essential for triggering receptor activity. Compounds 5 and 15 (50-100 microM) inhibited both TFLLR-amide (10 microM) and thrombin-mediated (0.5 and 1 U/ml; 5 and 10 microM) calcium signaling in a cultured human HEK cell assay.
authors.affiliation: Department of Chemistry, University of Patras, 26500, Patras, Greece.
authors.forename: Maria-Eleni
authors.initials: ME
authors.lastname: Androutsou
authors.forename: Mahmoud
authors.initials: M
authors.lastname: Saifeddine
authors.forename: Morley D
authors.initials: MD
authors.lastname: Hollenberg
authors.forename: John
authors.initials: J
authors.lastname: Matsoukas
authors.forename: George
authors.initials: G
authors.lastname: Agelis
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001120:Arginine / Q000031:analogs & derivatives / Q000737:chemistry; D020013:Calcium Signaling / Q000187:drug effects; D002460:Cell Line; D003510:Cyclohexanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004151:Dipeptides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006146:Guanidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry; D044463:Receptor, PAR-1 / Q000819:agonists / Q000737:chemistry*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D000577:Amides; C090291:C186 65; D003510:Cyclohexanes; D004151:Dipeptides; D004791:Enzyme Inhibitors; D006146:Guanidines; D007211:Indoles; D008024:Ligands; D009842:Oligopeptides; C462999:PAR-1-activating peptide; D010446:Peptide Fragments; D044463:Receptor, PAR-1; D018179:Receptors, Thrombin; D010649:Phenylalanine; D001120:Arginine; D013917:Thrombin