Novel RGD analogs as antithrombotic agents

Klein, Scott I.; Molino, Bruce F.; Chu, Valeria; Ruggeri, Zaverio M.; Czekaj, Mark; Gardner, Charles J.; Newman, Jack; Barrett, John

doi:10.1007/978-94-011-3034-9_157

Cited by 4 publications

(6 citation statements)

References 4 publications

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“…So far only little information about peptide mimetics interfering with fibrinogen binding to GP Ilb-IIIa has been published. 23 Our goal was to find molecules which (i) are as potent as the snake venom polypeptides but significantly smaller in size, (ii) have shorter plasma half-lives than monoclonal antibodies,11 and (iii) display selectivity for the fibrinogen receptor GP Ilb-IIIa versus the vitronectin receptor av/3a in the same order as the snake venom polypeptide barbourin.24 Initial structure-activity relationship studies with tetrapeptides of the type RGDX (X = Ser (1), Phe (2), Val…”

Section: Introductionmentioning

confidence: 99%

Low molecular weight, non-peptide fibrinogen receptor antagonists

Alig

Edenhofer²,

Hadváry³

et al. 1992

J. Med. Chem.

187

120

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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.

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Section: Introductionmentioning

confidence: 99%

Low molecular weight, non-peptide fibrinogen receptor antagonists

Alig

Edenhofer²,

Hadváry³

et al. 1992

J. Med. Chem.

187

120

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“…This rapidly revealed a number of modifications which resulted in either retention or enhancement of in vitro potency with regard to the inhibition of platelet aggregation. These modifications included the elimination of the terminal amino group, replacement of arginine with homoarginine, and alkylation of the glycine nitrogen . Combination and optimization of these features led to compound 1 (Figure ).…”

Section: Resultsmentioning

confidence: 99%

“…Attention was then focused on the basic guanidino group. Previously it was demonstrated that replacement of the guanidine of the arginine side chain in peptide analogues of RGDV with basic heterocycles, such as piperidine and imidazole, improves in vitro antiaggregatory activity. Piperidine-containing analogues had proven to be the most potent of these and have successfully been applied to nonpeptide GP IIb/IIIa antagonists .…”

Section: Resultsmentioning

confidence: 99%

“…These modifications included the elimination of the terminal amino group, replacement of arginine with homoarginine, and alkylation of the glycine nitrogen. 12 Combination and optimization of these features led to compound 1 (Figure 1). This analogue inhibited platelet aggregation with an IC 50 of 470 nM and abolished cyclic flow reductions in a canine model 13 of coronary artery occlusion upon parenteral administration of a bolus dose of 30 µg/kg followed by an infusion of 3 µg/kg/min for 60 min.…”

Section: Resultsmentioning

confidence: 99%

“…The saturated versions of 10 and 11, which incorporate β-(1-decalinyl)alanine (12) and β-(2-decalinyl)alanine ( 13) at the carboxy terminus, were prepared next and showed oral efficacy similar to 7. A comparison of the oral efficacy observed for the analogues containing naphthylalanines relative to those containing decalinylalanines (10 vs 12 and 11 vs 13) mirrors what was observed for the two derivatives containing phenylalanine and cyclohexylalanine (6 vs 7).…”

Section: Resultsmentioning

confidence: 99%

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Design of a New Class of Orally Active Fibrinogen Receptor Antagonists

et al. 1998

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The integrin receptor recognition sequence Arg-Gly-Asp was successfully used as a template from which to develop a series of potent, selective, orally active, peptide-based fibrinogen receptor antagonists with a long duration of action. Simple modifications centered on the Arg and Gly residues quickly led to a modified peptide (1) with significantly enhanced ability to inhibit in vitro platelet aggregation. Substitution of the guanidino group in 1 by piperidine provided 3, which showed not only a further increase in potency but also a modest degree of oral efficacy. Finally, exploration of the nature of the C-terminal amino acid, with respect to its side-chain functionality and the carboxy terminus, yielded a group of molecules that showed excellent in vitro potency for inhibiting platelet aggregation, excellent integrin selectivity, a high level of oral efficacy, and an extended duration of action.

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Pharmacophore refinement of gpIIb/IIIa antagonists based on comparative studies of antiadhesive cyclic and acyclic RGD peptides

Müller

Gurrath

Kessler

1994

J Computer-Aided Mol Des

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Structurally guided design approaches to low-molecular-weight platelet aggregation antagonists addressing the platelet-associated heterodimeric cell surface receptor gpIIb/IIIa rely on comparative studies of an ensemble of conformationally and biologically characterized compounds, since no high-resolution structure of the receptor system is available. We report a classical indirect and comparative pharmacophore refinement approach based on a series of small cyclic Arg-Gly-Asp (RGD) peptides as gpIIb/IIIa-fibrinogen interaction antagonists. These peptides have previously been investigated as potent and selective tumor cell adhesion inhibitors. The definition of geometrical descriptors classifying the RGD peptide conformations and their subsequent analysis over selected RGD- and RXD-containing protein structures allows for a correlation of distinct structural features for platelet aggregation inhibition. An almost parallel alignment of the Arg and Asp side chains was identified by a vector analysis as being present in all active cyclic hexa- and pentapeptides. This orientation is induced mainly by the constraint of backbone cyclization and is not of any covalent tripeptide-inherent origin, which was rationalized by a 500 ps high-energy MD simulation of a sequentially related linear model peptide. The incorporation of the recognition tripeptide Arg-Gly-Asp into the cyclic peptide templates acted as a filter mechanism, restricting the otherwise free torsional relation of both side chains to a parallel orientation. Based on the derived results, several detailed features of the receptor binding site could be deduced in terms of receptor complementarity. These findings should govern the design of next-generation compounds with enhanced activities. Furthermore, the complementary stereochemical characteristics of the substrate can be used as boundary conditions for pseudoreceptor modelling studies that are capable of reconstructing a hypothetical binding pocket, qualitatively resembling the steric and electronic demands of gpIIb/IIIa. It is interesting to note that these features provide clear differentiation to requirements for inhibition of alpha v beta 3 substrate binding. This can account for the extremely high selectivity and activity of some of our constrained peptides for either the alpha IIb beta 3 or the alpha v beta 3 receptor.

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Novel RGD analogs as antithrombotic agents

Cited by 4 publications

References 4 publications

Low molecular weight, non-peptide fibrinogen receptor antagonists

Low molecular weight, non-peptide fibrinogen receptor antagonists

Design of a New Class of Orally Active Fibrinogen Receptor Antagonists

Pharmacophore refinement of gpIIb/IIIa antagonists based on comparative studies of antiadhesive cyclic and acyclic RGD peptides

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