Bradykinin receptor antagonists – a review of the patent literature 2005 – 2008

Fincham, Christopher I.; Bressan, A.; Paris, Marielle; Rossi, Cristina; Fattori, Daniela

doi:10.1517/13543770902994389

Cited by 28 publications

(19 citation statements)

References 41 publications

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“…Icatibant is a selective bradykinin B2 receptor antagonist 15,16 with, like bradykinin itself, an affinity for the B2 receptor. It does not interact with bradykinin B1 receptors or other peptide receptors.…”

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confidence: 99%

Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

Cicardi¹,

Banerji²,

Bracho³

et al. 2010

N Engl J Med

477

385

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BACKGROUND Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P = 0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

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mentioning

confidence: 99%

Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

Cicardi¹,

Banerji²,

Bracho³

et al. 2010

N Engl J Med

477

385

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“…SSR240612 is a stable and highly selective blocker of des-Arg 9 BK binding at B 1 R with a K i of 0.48 nM, which was previously tested in man for neuropathic pain [24]. …”

Section: Methodsmentioning

confidence: 99%

Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer’s disease mice

Lacoste

Tong

Lahjouji

et al. 2013

J Neuroinflammation

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BackgroundRecent evidence suggests that the inducible kinin B1 receptor (B1R) contributes to pathogenic neuroinflammation induced by amyloid-beta (Aβ) peptide. The present study aims at identifying the cellular distribution and potentially detrimental role of B1R on cognitive and cerebrovascular functions in a mouse model of Alzheimer’s disease (AD).MethodsTransgenic mice overexpressing a mutated form of the human amyloid precursor protein (APPSwe,Ind, line J20) were treated with a selective and brain penetrant B1R antagonist (SSR240612, 10 mg/kg/day for 5 or 10 weeks) or vehicle. The impact of B1R blockade was measured on i) spatial learning and memory performance in the Morris water maze, ii) cerebral blood flow (CBF) responses to sensory stimulation using laser Doppler flowmetry, and iii) reactivity of isolated cerebral arteries using online videomicroscopy. Aβ burden was quantified by ELISA and immunostaining, while other AD landmarks were measured by western blot and immunohistochemistry.ResultsB1R protein levels were increased in APP mouse hippocampus and, prominently, in reactive astrocytes surrounding Aβ plaques. In APP mice, B1R antagonism with SSR240612 improved spatial learning, memory and normalized protein levels of the memory-related early gene Egr-1 in the dentate gyrus of the hippocampus. B1R antagonism restored sensory-evoked CBF responses, endothelium-dependent dilations, and normalized cerebrovascular protein levels of endothelial nitric oxide synthase and B2R. In addition, SSR240612 reduced (approximately 50%) microglial, but not astroglial, activation, brain levels of soluble Aβ1-42, diffuse and dense-core Aβ plaques, and it increased protein levels of the Aβ brain efflux transporter lipoprotein receptor-related protein-1 in cerebral microvessels.ConclusionThese findings show a selective upregulation of astroglial B1R in the APP mouse brain, and the capacity of the B1R antagonist to abrogate amyloidosis, cerebrovascular and memory deficits. Collectively, these findings provide convincing evidence for a role of B1R in AD pathogenesis.

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“…BK, through the B2R, contributes to the chronic inflammatory response in the knee osteoarhritis, activating different cells, including synovial cells or chondrocytes, and inducing the release of pro-inflammatory cytokines, as well as the products of ciclooxygenase (COX) and lipooxygenase (LOX) [10], [11]. Several peptide and non-peptide B2R antagonists have been synthesised [12], [13]. Icatibant, a peptide compound, is one of the first B2R antagonists synthesised, now approved for the therapy of hereditary angio-oedema attacks [7], [14].…”

Section: Introductionmentioning

confidence: 99%

Antagonism of Bradykinin B2 Receptor Prevents Inflammatory Responses in Human Endothelial Cells by Quenching the NF-kB Pathway Activation

et al. 2014

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BackgroundBradykinin (BK) induces angiogenesis by promoting vessel permeability, growth and remodeling. This study aimed to demonstrate that the B2R antagonist, fasitibant, inhibits the BK pro-angiogenic effects.MethodologyWe assesed the ability of fasibitant to antagonize the BK stimulation of cultured human cells (HUVEC) and circulating pro-angiogenic cells (PACs), in producing cell permeability (paracellular flux), migration and pseocapillary formation. The latter parameter was studied in vitro (matrigel assay) and in vivo in mice (matrigel plug) and in rat model of experimental osteoarthritis (OA). We also evaluated NF-κB activation in cultured cells by measuring its nuclear translocation and its downstream effectors such as the proangiogenic ciclooxygenase-2 (COX-2), prostaglandin E-2 and vascular endothelial growth factor (VEGF).Principal findingsHUVEC, exposed to BK (1–10 µM), showed increased permeability, disassembly of adherens and tight-junction, increased cell migration, and pseudocapillaries formation. We observed a significant increase of vessel density in the matrigel assay in mice and in rats OA model. Importantly, B2R stimulation elicited, both in HUVEC and PACs, NF-κB activation, leading to COX-2 overexpression, enhanced prostaglandin E-2 production. and VEGF output. The BK/NF-κB axis, and the ensuing amplification of inflammatory/angiogenic responses were fully prevented by fasitibant as well as by IKK VII, an NF-κB. Inhibitor.ConclusionThis work illustrates the role of the endothelium in the inflammation provoked by the BK/NF-κB axis. It also demonstates that B2R blockade by the antaogonist fasibitant, abolishes both the initial stimulus and its amplification, strongly attenuating the propagation of inflammation.

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Bradykinin receptor antagonists – a review of the patent literature 2005 – 2008

Cited by 28 publications

References 41 publications

Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

Icatibant, a New Bradykinin-Receptor Antagonist, in Hereditary Angioedema

Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer’s disease mice

Antagonism of Bradykinin B2 Receptor Prevents Inflammatory Responses in Human Endothelial Cells by Quenching the NF-kB Pathway Activation

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