title: Low molecular weight, non-peptide fibrinogen receptor antagonists.
abstract: The tetrapeptide H-Arg-Gly-Asp-Ser-OH (1) (RGDS), representing a recognition sequence of fibrinogen for its platelet receptor GP IIb-IIIa (integrin alpha IIb beta 3), served as lead compound for the development of highly potent and selective fibrinogen receptor antagonists. Replacement of the N-terminal arginine by p-amidinophenylalanine or the Gly moiety by m-aminobenzoic acid led to compounds which are superior to the lead peptide with regard to activity and selectivity for GP IIb-IIIa vs the closely related vitronectin receptor alpha v beta 3. By random screening [(p-amidinobenzenesulfonamido)ethyl]-p-phenoxyacetic acid derivatives have been identified as fibrinogen receptor antagonists. Further structure-activity relationship studies culminated in the preparation of N-[N-[N-(p-amidinobenzoyl)-beta-alanyl]-L-alpha-aspartyl]-3-phenyl-L- alanine (29h, Ro 43-5054) and [[1-[N-(p-amidinobenzoyl)-L-tyrosyl]-4-piperidinyl]oxy]acetic acid (37f, Ro 44-9883), which exhibit very high activity as platelet aggregation inhibitors (IC50s 0.06 and 0.03 microM, respectively, human PRP/ADP) as well as marked selectivity for GP IIb-IIIa vs alpha v beta 3. Since the activity of 37f in dogs declines according to a two-compartment model with an initial phase having a t1/2 of 8 min and a second phase with a t1/2 of 110 min, this compound is a suitable candidate for the development as iv platelet inhibitor.
authors.affiliation: Pharma Division, Preclinical Research, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Alig
authors.forename: A
authors.initials: A
authors.lastname: Edenhofer
authors.forename: P
authors.initials: P
authors.lastname: Hadváry
authors.forename: M
authors.initials: M
authors.lastname: Hürzeler
authors.forename: D
authors.initials: D
authors.lastname: Knopp
authors.forename: M
authors.initials: M
authors.lastname: Müller
authors.forename: B
authors.initials: B
authors.lastname: Steiner
authors.forename: A
authors.initials: A
authors.lastname: Trzeciak
authors.forename: T
authors.initials: T
authors.lastname: Weller
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D004285:Dogs; D005340:Fibrinogen / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010980:Platelet Membrane Glycoproteins / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D010980:Platelet Membrane Glycoproteins; D005340:Fibrinogen