2 Fibrinogen Receptor Antagonists: Design and Clinical Applications

Eldred, Colin; Judkins, Brian D.

doi:10.1016/s0079-6468(08)70045-6

Cited by 15 publications

(7 citation statements)

References 157 publications

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“…10 distance ranges were used for the 4-point pharmacophores, in conjunction with the pharmacophore atom types mentioned in section 2.2, resulting in a binary key with 24.4 x 10 6 theoretically accessible pharmacophores. The pharmacophore fingerprint from the known tripeptide RGD motif Fibrinogen uses for receptor binding [129] was then used to screen the database, which had been seeded with fibrinogen receptor antagonists covering a widerange of structural classes (see Fig. (5)).…”

Section: -And 4-point Pharmacophore Fingerprints (Multiple Pharmacopmentioning

confidence: 99%

3-D Pharmacophores in Drug Discovery

Mason¹,

Good²,

Martin³

2001

CPD

228

147

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In this chapter we review the use of 3-D pharmacophores in drug discovery. Recent advances are highlighted, including the application of pharmacophore descriptors generated both from ligands and protein binding sites. The application of 3-D pharmacophore fingerprints as molecular descriptors for similarity and diversity applications such as virtual screening, library design and QSAR is discussed. In addition, we highlight the quantification of structure-based diversity using site-derived fingerprints, and review virtual screening methods using both single refined hypotheses and the fingerprints of multiple potential hypotheses. Further, we discuss methods that take protein flexibility and molecular shape-into account. Each of the above techniques are reviewed with particular reference to the recent advances, advantages and challenges of each methodology.

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Section: -And 4-point Pharmacophore Fingerprints (Multiple Pharmacopmentioning

confidence: 99%

3-D Pharmacophores in Drug Discovery

Mason¹,

Good²,

Martin³

2001

CPD

228

147

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“…It is undoubtedly the major factor in haemostasis, mediating the response to tissue injury. In the coagulation cascade, thrombin truncates fibrinogen to fibrin, which is readily cross-linked to form a physical block-a haemostatic plug [1,2,3,4]. Thrombin is also the most potent platelet activator in vivo, leading to release of proaggregatory mediators and expression of platelet adhesion receptors (selectins, integrins) [1,3,4,5,6].…”

Section: Thrombin-protease That Triggers a Variety Of Cellular Responmentioning

confidence: 99%

“…In the coagulation cascade, thrombin truncates fibrinogen to fibrin, which is readily cross-linked to form a physical block-a haemostatic plug [1,2,3,4]. Thrombin is also the most potent platelet activator in vivo, leading to release of proaggregatory mediators and expression of platelet adhesion receptors (selectins, integrins) [1,3,4,5,6]. In vascular smooth muscle cells, along with endothelial cells and fibroblasts, thrombin induces contraction and proliferation with simultaneous release of vasoconstrictors, mitogens, chemotactics and inflammatory mediators [4,5,6,7].…”

Section: Thrombin-protease That Triggers a Variety Of Cellular Responmentioning

confidence: 99%

Thrombin Receptor Antagonists, Recent Advances in PAR-1 Antagonist Development

Anderluh

Dolenc²

2002

CMC

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The receptor for the serine protease thrombin, the protease-activated receptor-1 (PAR-1), has been recently characterized. Its key roles in thrombin-stimulated human platelet activation, vascular endothelial and smooth muscle proliferation, inflammatory responses and neurodegeneration suggest receptor involvement in various disorders such as arterial thrombosis, atherosclerosis, restenosis, inflammation and myocardial infarction. It has been established that thrombin elicits the majority of its effects via PAR-1. PAR-1 has a novel mechanism of activation. The receptor, a member of the seven-transmembrane domain receptor family, is cleaved by thrombin at a specific site on the N-terminal extension, and a newly exposed N-terminus acts as a tethered ligand to activate the receptor itself. The need for development of a PAR-1 antagonist that may be valuable as a therapeutic agent has been recognized. An intriguing challenge is the necessity of the antagonist to compete with an intramolecular ligand while showing no intrinsic activity. The lead compounds were found to be synthetic peptides containing N-terminal hexapeptide or pentapeptide (Ser-Phe-Leu-Leu-Arg-Asn, Ser-Phe-Leu-Leu-Arg) or modified sequences (TRAPs; thrombin receptor-activating peptides), which exhibit full PAR-1 agonist activity. Selective PAR-1 antagonists have already been synthesized. Though their potency is still not enough to justify therapeutic use, it is clear that future progress will bring a novel class of drugs-thrombin receptor antagonists. The emphasis of this review, therefore, will be placed on advances in the discovery of potent and selective PAR-1 antagonists.

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“…Fibrinogen binds to its receptor via the RGD motif. 51 Solution NMR and crystal structures of the fibronectin type III domain containing this motif [52][53][54] show it to be located in a disordered loop region, suggesting a degree of flexibility. A number of compounds have been identified as fibrinogen receptor antagonists covering a wide range of structural classes; 55 see Figure 6.…”

Section: Multipharmacophore Searchingsfocused Library Designmentioning

confidence: 99%

Enhancing the Hit-to-Lead Properties of Lead Optimization Libraries

Pickett¹,

McLay²,

Clark³

1999

J. Chem. Inf. Comput. Sci.

104

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In this paper we address several issues in the design of lead optimization libraries. Multipharmacophore descriptors were first developed in the context of designing diverse compound libraries. One reason for favoring such descriptors is the importance of the pharmacophore hypothesis in understanding the interaction of a compound with a protein target. Allied to this is the proposal that sampling over all potential pharmacophores leads to diversity in a biologically relevant space. We present results in support of this argument and also demonstrate that such methods are applicable to the design of focused libraries where the aim is to design the library toward a known lead or leads. This portability is important because it means that the same descriptors can be used for diverse library design, screening set selection, and focused library design, giving a consistent approach. We also examine the question of designing libraries with improved pharmacokinetic properties and show that it is possible to derive simple and rapidly computable descriptors applicable to the prediction of drug transport properties. Furthermore, these can be applied in the context of library design, although it may be necessary to synthesize libraries in a noncombinatorial manner to obtain the best results. To address this problem, we describe a Monte Carlo search procedure that allows the selection of a near-combinatorial subset in which all library members satisfy the design criteria. We present an example from our own work that illustrates how consideration of calculated log P, molecular weight, and polar surface area in the design of a combinatorial library can lead to compounds with improved absorption characteristics as determined by experimental Caco-2 measurements.

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2 Fibrinogen Receptor Antagonists: Design and Clinical Applications

Cited by 15 publications

References 157 publications

3-D Pharmacophores in Drug Discovery

3-D Pharmacophores in Drug Discovery

Thrombin Receptor Antagonists, Recent Advances in PAR-1 Antagonist Development

Enhancing the Hit-to-Lead Properties of Lead Optimization Libraries

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