Benzodiazepines as Potent and Selective Bradykinin B<sub>1</sub> Antagonists

Wood, Michael R.; Kim, June J.; Han, Wei; Dorsey, Bruce D.; Homnick, Carl F.; DiPardo, Robert M.; Kuduk, Scott D.; MacNeil, Tanya; Murphy, Kathy; Lis, Edward; Ransom, Richard W.; Stump, Gary L.; Lynch, Joseph J.; O’Malley, Stacey; Miller, Patricia; Chen, Tsing-Bau; Harrell, C. Meacham; Chang, Raymond S.L.; Sandhu, Punam; Ellis, Joan D.; Bondiskey, Peter J.; Pettibone, Douglas J.; Freidinger, Roger; Bock, Mark G.

doi:10.1021/jm034020y

Cited by 57 publications

(32 citation statements)

References 14 publications

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“…Wood et al (2003) described the in vitro and in vivo properties of a series of benzodiazepine-based compounds. The preferred structure from this series, Compound 12 (Fig.…”

Section: Nonpeptide Ligandsmentioning

confidence: 99%

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Marceau²,

et al. 2005

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“…Wood et al (2003) described the in vitro and in vivo properties of a series of benzodiazepine-based compounds. The preferred structure from this series, Compound 12 (Fig.…”

Section: Nonpeptide Ligandsmentioning

confidence: 99%

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Marceau²,

et al. 2005

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“…To confirm the involvement of kinin receptors in the contractile response of pig iris sphincter to des-Arg 9 -bradykinin after lipopolysaccharide incubation, CRCs were obtained in the absence or presence of selective kinin B 1 and B 2 receptor antagonists. Preparations were exposed continuously to lipopolysaccharide for 4 h, and then they were incubated with the selective B 2 receptor antagonist Hoe 140 (30 nM) or with the selective peptide B 1 receptor antagonists des-Arg 9 [Leu 8 ]-bradykinin (3-30 M) and R-715 (1-10 nM) or the novel nonpeptide B 1 receptor antagonist with a benzodiazepine core (3-30 nM) (Wood et al, 2003). Only one CRC was plotted for each preparation.…”

Section: Drugs Andmentioning

confidence: 99%

Mechanisms Underlying Lipopolysaccharide-Induced Kinin B₁Receptor Up-Regulation in the Pig Iris Sphincter in Vitro

Sayah¹,

Medeiros²,

Fernandes³

et al. 2006

Mol Pharmacol

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Kinin B 1 receptors are known to be highly induced after inflammatory stimuli in several biological systems. We report that incubation of pig iris sphincter with lipopolysaccharide from Escherichia coli caused a marked and time-related up-regulation of B 1 , accompanied by a reduction of B 2 receptor-mediated contractile responses. The up-regulation of B 1 receptors by lipopolysaccharide stimulation was decreased by the inhibitors of protein synthesis, cycloheximide and actinomycin D, and by dexamethasone and the nuclear factor-B (NF-B) inhibitor pyrrolidinedithiocarbamate (PDTC). In addition, lipopolysaccharide-induced up-regulation of B 1 receptors in the pig iris sphincter was significantly reduced by the p38 inhibitor 4-(4-fluorophenyl)-2-(4-methylsulfinylphenyl)-5-(4-pyridyl)1H-imidazole (SB203580) and to a lesser extent by the extracellular signal-regulated kinases 1 and 2 (ERK1/2) blocker 2Ј-amino-3Ј-methoxyflavone (PD98059). Molecular biology experiments demonstrated that in vitro incubation with lipopolysaccharide resulted in a time-dependent and remarkable activation of NF-B and of p38 and ERK1/2 mitogen-activated protein (MAP) kinases, in pig iris sphincter preparations. While attempting to verify how MAP kinases are part of the B 1 receptor-activated signaling transduction pathways, we observed that PD98059 was able to markedly reduce the contraction induced by B 1 receptor activation in lipopolysaccharide-pretreated pig iris sphincter muscle but that this response was only partially decreased by SB203580. Our results extend the previous evidence on the mechanisms underlying the B 1 receptor upregulation processes and demonstrate for the first time how this takes place in an ocular tissue, the pig iris sphincter. It is therefore possible to define B 1 receptors as therapeutic targets for the treatment of infectious and inflammatory alterations of the eye.

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“…A benzodiazepine-based antagonist programme was Merck's first foray into BK B 1 medicinal chemistry, and the subsequent patent application lists ∼ 80 examples, most of which incorporate a C-3 urea link by virtue of the coupling chemistry employed in their syntheses [87,179]. Screening of an inhouse sample collection led to the identification of the racemic benzodiazepine (74; Figure 17) as an antagonist of the hB 1 R. The compound exhibited a K i value of 28 nM in a binding assay in CHO cells stably expressing the hB 1 R and its in vitro functional activity (IC 50 ) against hB 1 Rs was 164 nM.…”

Section: Benzodiazepine Derivativesmentioning

confidence: 99%

Non-peptide ligands for bradykinin receptors 1995 – 2004

Dziadulewicz

2005

Expert Opinion on Therapeutic Patents

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It has been a decade since the area of bradykinin (BK) research was last reviewed in this journal. Within this period of time, selective, high-affinity non-peptide BK ligands have been identified by different research groups for both the B 1 and B 2 receptors (B 1 R and B 2 R). The efficacies of these agents in animal models of human diseases suggest that it may be possible to develop such compounds into novel classes of therapeutic drugs. The emerging pharmacological evidence from these studies suggests that B 1 R and B 2 R antagonists may be clinically useful for the treatment of pain, inflammation, cancer, hypotension, asthma, colitis, rhinitis, pancreatitis, sepsis and rheumatoid arthritis. B 2 R agonists, on the other hand, may alleviate cardiovascular disorders, such as congestive heart failure, hypertension and ischaemic heart disease, and are potentially useful for the treatment of diabetic disorders by mimicking the beneficial effects of BK on glucose uptake and insulin sensitivity. A major challenge in targeting the B 2 R is maintaining a balance between the opposing beneficial (cardioprotective, anti-inflammatory) and debilitating (pro-inflammatory, cardiocompromising) effects upon activation or inhibition of this receptor subtype. For this reason, the last few years have seen a significant shift in research emphasis to the B 1 R subtype due to its disease-dependent expression. This review will focus on the advances in BK medicinal chemistry reported between 1995 and the beginning of December 2004, with particular emphasis on small-molecule patent disclosures made during this period.

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Benzodiazepines as Potent and Selective Bradykinin B₁ Antagonists

Cited by 57 publications

References 14 publications

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Mechanisms Underlying Lipopolysaccharide-Induced Kinin B₁Receptor Up-Regulation in the Pig Iris Sphincter in Vitro

Non-peptide ligands for bradykinin receptors 1995 – 2004

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Benzodiazepines as Potent and Selective Bradykinin B1 Antagonists

Cited by 57 publications

References 14 publications

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

Mechanisms Underlying Lipopolysaccharide-Induced Kinin B1Receptor Up-Regulation in the Pig Iris Sphincter in Vitro

Non-peptide ligands for bradykinin receptors 1995 – 2004

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Product

Resources

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Benzodiazepines as Potent and Selective Bradykinin B₁ Antagonists

Mechanisms Underlying Lipopolysaccharide-Induced Kinin B₁Receptor Up-Regulation in the Pig Iris Sphincter in Vitro