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.
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.
Androutsou
Maria-Eleni
ME
Department of Chemistry, University of Patras, 26500, Patras, Greece.
Saifeddine
Mahmoud
M
Hollenberg
Morley D
MD
Matsoukas
John
J
Agelis
George
G
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
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