Pharmacological profile of LF 16-0687, a new potent non-peptide bradykinin B2 receptor antagonist

Pruneau, Didier; Paquet, Jean Luc; Luccarini, Jean‐Michel; Defrêne, Evelyne; Fouchet, Chantal; Franck, Rose‐Marie; Loillier, Bruno; Robert, Claude; Bélichard, Pierre; Duclos, H; Cremers, Béatrice; Dodey, Pierre

doi:10.1016/s0162-3109(99)00128-9

Cited by 85 publications

(65 citation statements)

References 21 publications

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“…Previously known as LF 16-0687 (3 in Figure 1), anatibant is a potent B2 antagonist of Fournier with a IC50 of 0.67 nM at the human receptor [23]. The compound shares the 8-benzyloxy-2-methyl-quinoline moiety with the two antagonists described above, and in this case linked to a pyrrolidine sulfonamide with a 4-amidinofenil moiety as charged terminal group.…”

Section: Anatibantmentioning

confidence: 96%

“…Specifically, WIN64338 developed at Sterling Winthrop was the first BK B2 non-peptide antagonist disclosed (4 in Figure 1) [20]. Other compounds were disclosed in the following years, including a series of compounds developed by Fujisawa, like FR173657 (2 in Figure 1) [21]; bradyzide developed by Novartis (5 in Figure 1) [22]; anatibant developed by Fournier (3 in Figure 1) [23] or fasitibant developed by Menarini (1 in Figure 1) [24]. These compounds are high affinity BK B2 selective antagonists with limited oral bioavailability.…”

Section: Introductionmentioning

confidence: 99%

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New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding

Lupala

Gómez-Gutiérrez

Pérez

2015

J Comput Aided Mol Des

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Abstract:Bradykinin (BK) is a member of the kinin family, released in response to inflammation, trauma, burns, shock, allergy and some cardiovascular diseases, provoking vasodilatation and increased vascular permeability among other effects. Their actions are mediated through at least two G-protein coupled receptors, B1 a receptor upregulated during inflammation episodes or tissue trauma and B2 that is constitutively expressed in a variety of cell types. The goal of the present work is to carry out a structure-activity study of BK B2 antagonism, taking into account the stereochemical features of diverse non-peptide antagonists and the way these features translate into ligand anchoring points to complementary regions of the receptor, through the analysis of the respective ligand-receptor complex. For this purpose an atomistic model of the BK B2 receptor was built by homology modeling and subsequently refined embedded in a lipid bilayer by means of a 600 ns molecular dynamics trajectory. The average structure from the last hundred nanoseconds of the molecular dynamics trajectory was energy minimized and used as model of the receptor for docking studies. For this purpose, a set of compounds with antagonistic profile, covering maximal diversity were selected from the literature. Specifically, the set of compounds include Fasitibant, FR173657, Anatibant, WIN64338, Bradyzide, CHEMBL442294, and JSM10292. Molecules were docked into the BK B2 receptor model and the corresponding complexes analyzed to understand ligand-receptor interactions. The outcome of this study is summarized in a 3D pharmacophore that explains the observed structureactivity results and provides insight into the design of novel molecules with antagonistic profile. To prove the validity of the pharmacophore hypothesized a virtual screening process was also carried out. The pharmacophore was used as query to identify new hits using diverse databases of molecules. The results of this study revealed a set of new hits with structures not connected to the molecules used for pharmacophore development. A few of these structures were purchased and tested. The results of the binding studies show about a 33% success rate with a correlation between the number of pharmacophore points fulfilled and their antagonistic potency. Some of these Powered by Editorial Manager® and ProduXion Manager® from Aries Systems Corporationstructures are disclosed in the present work.Response to Reviewers: We sincerely appreciate the involvement of reviewer #1 and are deeply obliged. The reviewer was right in pointing the distortion of the ring and the amide in Figure 8 that has now been fixed in the revised version of Figure 8. We have also modified the viewpoint of Figure 9 to clearly show the protonation status of the terminal amine that was unfortunately hidden in the previous version of Figure 9 this study is summarized in a 3D pharmacophore that explains the observed structure-activity results and provides insight into the design of novel molecules with antagonistic profile. ...

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Section: Anatibantmentioning

confidence: 96%

Section: Introductionmentioning

confidence: 99%

New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding

Lupala

Gómez-Gutiérrez

Pérez

2015

J Comput Aided Mol Des

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“…1,2 The known B 2 R antagonists are sequence-related peptides 3,4 or nonpeptide compounds. 5,6 The introduction of the B 2 4 allowed a critical assessment of the role of kinin in the autoregulation of the circulation, blood pressure regulation, and the therapeutic effects of angiotensin-converting enzyme inhibitors, notably in clinical studies. 1,2 The competitive status of icatibant, verified in human tissues and cells, unexpectedly varied according to the species studied.…”

mentioning

confidence: 99%

“…In the present study, we investigated the competitive nature and reversibility of a constrained peptide structurally related to icatibant (NPC 17731, D-Arg[Hyp 3 , D-HypE(transpropyl) 7 , Oic 8 ]-BK) 11 and of a novel nonpeptide antagonist (LF 16.0687) 6 in the rabbit jugular vein; the behavior of B 2 R antagonists was correlated with events posterior to receptor binding in this species, with comparison to the wellestablished agonist-induced internalization of the B 2 R. 12 …”

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confidence: 99%

Antagonist-Induced Intracellular Sequestration of Rabbit Bradykinin B ₂ Receptor

et al. 2000

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Abstract-In a contractility assay based on the rabbit jugular vein, the structurally related drugs NPC 17731 or icatibant (1 to 3 nmol/L) were insurmountable antagonists of bradykinin (BK) B 2 receptors (B 2 Rs). After ample washing (3 hours), the antagonism exerted by these peptides was not reversible. By contrast, the antagonist LF 16.0687 (30 to 100 nmol/L) was competitive and reversible. A rabbit B 2 R-green fluorescent protein (B 2 R-GFP) conjugate was expressed in mammalian cells. In COS-1 cells, it exhibited an affinity for.61 nmol/L) similar to that of the wild-type rabbit B 2 R. The stably expressed construction in HEK-293 cells was functionally active (phospholipase A 2 assay), and the antagonists mentioned above retained their respective surmountable or insurmountable behavior. Competition of [3 H]BK binding to B 2 R-GFP by the antagonists or BK was largely reversible after a 3-hour washout period at 0°C; at 37°C, icatibant or NPC 17731 effects were not reversible. B 2 R-GFP was visualized in the plasma membranes of HEK-293 cells and rapidly internalized in response to BK. NPC 17731 or icatibant slowly translocated B 2 R-GFP into cells over 24 hours, whereas LF 16.0687 had no effect on the subcellular distribution of B 2 R-GFP. Cell extract immunoblotting with anti-GFP antibodies revealed a 101-to 105-kDa protein that was not significantly degraded on 24 hours of cell treatment with any of the ligands but was translocated in part to the 15 000-g pellet of the extract on treatment with BK or the noncompetitive antagonists. NPC 17731 and icatibant are noncompetitive, nonequilibrium antagonists that promote the cellular sequestration of rabbit B 2 R expressed in an heterologous system.

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“…propyl]-2(S)-pyrrolidinecarboxamide, mesylate salt), a previously described nonpeptide B 2 receptor antagonist [17], was a gift from Laboratoires Fournier (Daix, (mercaptomethyl-3-guanidinoethylthiopropanoic acid) from Calbiochem (La Jolla, CA). The latter compound is a high affinity inhibitor of arginine carboxypeptidases [19].…”

Section: Drugsmentioning

confidence: 99%

Met-Lys-bradykinin-Ser-Ser, a peptide produced by the neutrophil from kininogen, is metabolically activated by angiotensin converting enzyme in vascular tissue

Gera¹,

Roy²,

Bawolak³

et al. 2011

Pharmacological Research

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Bradykinin (BK) is a vasoactive nonapeptide cleaved from circulating kininogens and that is degraded by angiotensin converting enzyme (ACE). It has been reported that the PR3 protease from human neutrophil releases an alternate peptide of 13 amino acids, Met-Lys-BK-Ser-Ser, from high molecular weight kininogen. We have studied vascular actions of this kinin. Its affinity for recombinant B 1 and B 2 receptors is very low, as assessed by the binding competition of

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Pharmacological profile of LF 16-0687, a new potent non-peptide bradykinin B2 receptor antagonist

Cited by 85 publications

References 21 publications

New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding

New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding

Antagonist-Induced Intracellular Sequestration of Rabbit Bradykinin B ₂ Receptor

Met-Lys-bradykinin-Ser-Ser, a peptide produced by the neutrophil from kininogen, is metabolically activated by angiotensin converting enzyme in vascular tissue

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Pharmacological profile of LF 16-0687, a new potent non-peptide bradykinin B2 receptor antagonist

Cited by 85 publications

References 21 publications

New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding

New insights into the stereochemical requirements of the bradykinin B2 receptor antagonists binding

Antagonist-Induced Intracellular Sequestration of Rabbit Bradykinin B 2 Receptor

Met-Lys-bradykinin-Ser-Ser, a peptide produced by the neutrophil from kininogen, is metabolically activated by angiotensin converting enzyme in vascular tissue

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Antagonist-Induced Intracellular Sequestration of Rabbit Bradykinin B ₂ Receptor