LOW-MOLECULAR-WEIGHT, NONPEPTIDE FIBRINOGEN RECEPTOR ANTAGONISTS

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)beta3), served as lead compound for the development of highly potent and selective fibrinogen receptor antagonists. Replacement of the N-termi...

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Published inJournal of medicinal chemistry Vol. 35; no. 23; pp. 4393 - 4407
Main Authors ALIG, L, EDENHOFER, A, HADVARY, P, HURZELER, M, KNOPP, D, MULLER, M, STEINER, B, TRZECIAK, A, WELLER, T
Format Journal Article
LanguageEnglish
Published WASHINGTON Amer Chemical Soc 13.11.1992
Subjects
Chemistry, Medicinal
Life Sciences & Biomedicine
Pharmacology & Pharmacy
Science & Technology
GLYCOPROTEIN-IIB/IIIA
RGD PEPTIDE
COMPLEX
SPECIFICITY
THROMBIN
AMINO-ACIDS
PLATELET
IIIA ANTAGONIST
BINDING
ANTIPLATELET
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Summary: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)beta3), 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)beta3. 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 muM, respectively, human PRP/ADP) as well as marked selectivity for GP IIb-IIIa vs alpha(v)beta3. 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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00101a017