Irreversible enzyme inhibitors. CLII. Proteolytic enzymes. 10. Inhibition of guinea pig complement by substituted benzamidines

Baker, B. R.; Erickson, Edward H.

doi:10.1021/jm00303a016

Cited by 22 publications

(18 citation statements)

References 3 publications

(5 reference statements)

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“…Therapeutic inhibition of the human complement system is far from a recent concept, and the use of complement inhibitors for the treatment of arthritic diseases or transplantation-related complications was already suggested almost 50 years ago [1, 2]. Yet despite several breakthroughs and tremendous progress in target characterization and inhibitor design, the translation of this appealing proposition into the clinic has taken way more time and effort than anticipated [3–5].…”

Section: Introductionmentioning

confidence: 99%

New milestones ahead in complement-targeted therapy

Ricklin

Lambris

2016

Seminars in Immunology

125

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The complement system is a powerful effector arm of innate immunity that typically confers protection from microbial intruders and accumulating debris. In many clinical situations, however, the defensive functions of complement can turn against host cells and induce or exacerbate immune, inflammatory, and degenerative conditions. Although the value of inhibiting complement in a therapeutic context has long been recognized, bringing complement-targeted drugs into clinical use has proved challenging. This important milestone was finally reached a decade ago, yet the clinical availability of complement inhibitors has remained limited. Still, the positive long-term experience with complement drugs and their proven effectiveness in various diseases has reinvigorated interest and confidence in this approach. Indeed, a broad variety of clinical candidates that act at almost any level of the complement activation cascade are currently in clinical development, with several of them being evaluated in phase 2 and phase 3 trials. With antibody-related drugs dominating the panel of clinical candidates, the emergence of novel small-molecule, peptide, protein, and oligonucleotide-based inhibitors offers new options for drug targeting and administration. Whereas all the currently approved and many of the proposed indications for complement-targeted inhibitors belong to the rare disease spectrum, these drugs are increasingly being evaluated for more prevalent conditions. Fortunately, the growing experience from preclinical and clinical use of therapeutic complement inhibitors has enabled a more evidence-based assessment of suitable targets and rewarding indications as well as related technical and safety considerations. This review highlights recent concepts and developments in complement-targeted drug discovery, provides an overview of current and emerging treatment options, and discusses the new milestones ahead on the way to the next generation of clinically available complement therapeutics.

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Section: Introductionmentioning

confidence: 99%

New milestones ahead in complement-targeted therapy

Ricklin

Lambris

2016

Seminars in Immunology

125

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“…The 107 benzamidines used in this study are those presented in the work of Hansch and Yoshimoto − in which Baker and his students determined experimentally the inhibition of guinea pig complement by benzamidines. Hansch and Yoshimoto provide the structures and measured log 1/ C values, where C is the micromolar concentration for 50% inhibition of complement ( I 50 ), for 108 benzamidines.…”

Section: Methodsmentioning

confidence: 99%

Prediction of Complement-Inhibitory Activity of Benzamidines Using Topological and Geometric Parameters

Basak

Gute

Ghatak

1998

J. Chem. Inf. Comput. Sci.

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A hierarchical approach to quantitative structure-activity relationship (QSAR) modeling has been used to estimate the complement-inhibitory potency of 105 benzamidines. This hierarchical approach uses topostructural, topochemical, and geometric parameters in a stepwise fashion to build increasingly more complex models. The results show that topostructural indices alone, specifically I(D), predict inhibitory potency reasonably well. The addition of topochemical and geometrical parameters to the set of descriptors provides only marginal improvement in predictive power. However, when taken alone, the geometric parameter (3D)W provides a more stable model than the topostructural one.

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“…Complement-mediated hemolytic activities in the classical he molytic reaction system were determined as described by Baker and Erickson [9], and those in the alternative hemolytic reaction system by the method of Platts-MiUs and Ishizaka [10]. In the hemolytic reaction system for the classical pathway, sensitized sheep erythro cytes at a concentration of2.5x 10s cells/ml were lysed with 1/128 diluted guinea pig complement, 1/20 diluted rat complement or 1/30 diluted human serum, respectively.…”

Section: Inhibition O F Complement-mediated Hemolysismentioning

confidence: 99%

Inhibition of Various Immunological Reactions in vivo by a New Synthetic Complement Inhibitor

Hitomi¹,

Fujii²

1982

Int Arch Allergy Immunol

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FUT-175 (6-amidino-2-naphthyl-4-guanidino benzoate-dimethanesulfonate), a new synthetic protease inhibitor, inhibits the enzyme activities of various proteases, such as C1r, CĪ esterase, thrombin, kalli-krein, plasmin and trypsin. FUT-175 strongly inhibited complement-mediated hemolysis via the classical and alternative pathways. The effects of FUT-175 on various immunological reactions in vivo were studied. The minimal effective dose of FUT-175 in systemic Forssman shock in guinea pigs was 6.25 mg/kg i.p. and 25 mg/kg p.o. In passive Arthus reactions in rats, the effective dose was 25 mg/kg i.p. and 250 mg/kg p.o. FUT-175 also inhibited other immunological reactions, such as passive cutaneous anaphylaxis and delayed hypersensitivity. Furthermore, at a dose of 25 mg/kg i.p. it strongly protected mice from death in endotoxin shock.

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Irreversible enzyme inhibitors. CLII. Proteolytic enzymes. 10. Inhibition of guinea pig complement by substituted benzamidines

Cited by 22 publications

References 3 publications

New milestones ahead in complement-targeted therapy

New milestones ahead in complement-targeted therapy

Prediction of Complement-Inhibitory Activity of Benzamidines Using Topological and Geometric Parameters

Inhibition of Various Immunological Reactions in vivo by a New Synthetic Complement Inhibitor

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