Nonpeptide Bradykinin B2 Receptor Antagonist Research Articles

A Robust Bioassay of the Human Bradykinin B2 Receptor That Extends Molecular and Cellular Studies: The Isolated Umbilical Vein

Bradykinin (BK) has various physiological and pathological roles. Medicinal chemistry efforts targeted toward the widely expressed BK B2 receptor (B2R), a G-protein-coupled receptor, were primarily aimed at developing antagonists. The only B2R antagonist in clinical use is the peptide icatibant, approved to abort attacks of hereditary angioedema. However, the anti-inflammatory applications of B2R antagonists are potentially wider. Furthermore, the B2R antagonists notoriously exhibit species-specific pharmacological profiles. Classical smooth muscle contractility assays are exploited over a time scale of several hours and support determining potency, competitiveness, residual agonist activity, specificity, and reversibility of pharmacological agents. The contractility assay based on the isolated human umbilical vein, expressing B2R at physiological density, was introduced when investigating the first non-peptide B2R antagonist (WIN 64338). Small ligand molecules characterized using the assay include the exquisitely potent competitive antagonist, Pharvaris Compound 3 or the partial agonist Fujisawa Compound 47a. The umbilical vein assay is also useful to verify pharmacologic properties of special peptide B2R ligands, such as the carboxypeptidase-activated latent agonists and fluorescent probes. Furthermore, the proposed agonist effect of tissue kallikrein on the B2R has been disproved using the vein. This assay stands in between cellular and molecular pharmacology and in vivo studies.

Ocular Hypotensive Activity of a Non-Peptide Bradykinin B2-Receptor Antagonist (WIN-64338) In Dutch-Belt Rabbits- A Case of Poly-Pharmacology in Action

Ocular Hypotensive Activity of a Non-Peptide Bradykinin B2-Receptor Antagonist (WIN-64338) In Dutch-Belt Rabbits- A Case of Poly-Pharmacology in Action

The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury

BackgroundCerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor.MethodsAdults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE), mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS), the Disability Rating Scale (DRS) and a modified version of the Oxford Handicap Scale (HIREOS).Results228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163) in the combined Anatibant treated group, compared to 19.3% (11/57) in the placebo group (relative risk = 1.37; 95% CI 0·76 to 2·46). All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36). The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures.ConclusionThis trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in the risk of serious adverse events was reduced. This trial provides no reliable evidence of benefit or harm and a larger trial would be needed to establish safety and effectiveness.Trial RegistrationThis study is registered as an International Standard Randomised Controlled Trial, number ISRCTN23625128.

Design and Synthesis of Novel Sulfonamide-Containing Bradykinin hB2 Receptor Antagonists. 2. Synthesis and Structure−Activity Relationships of α,α-Cycloalkylglycine Sulfonamides

Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.

Discovery of Non‐Peptide Bradykinin B2 Receptor Antagonists and Agonists

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access the actual ChemInform Abstract, please click on HTML or PDF.

非ペプチド性ブラジキニンＢ２受容体アンタゴニストおよびアゴニストの創製

A novel class of potent and selective non-peptide bradykinin (BK) B2 receptor antagonists and agonists was designed and synthesized. The unique screening lead (9) was discovered by a two-step directed random screening process. Systematic chemical modification of 9 elucidated the structural requirements essential for the B2 binding affinity, leading to the identification of the basic framework of this new series of B2 antagonists. A molecular modeling study suggested the key role of the N-methylanilide moiety at the 3-position of the 2, 6-dichlorophenyl ring to allow these compounds to adopt the characteristic active conformation. It was further revealed that the 4-substituent of the quinoline moiety is the key pharmacophore to determine the agonist/antagonist profiles. During these studies, we discovered the orally active non-peptide B2 antagonist, FK 3657 (2), which is undergoing clinical development, and potent B2 agonists represented by FR 190997 (5) and FR 198100 (6).

Beneficial effects of combined blockade of ACE and AT1 receptor on intimal hyperplasia in balloon-injured rat artery.

The present study was undertaken to elucidate the effect of the ACE inhibitor and the angiotensin II type 1 (AT1) receptor antagonist in combination on neointimal hyperplasia after balloon injury. Temocapril (an ACE inhibitor), CS-866 (an AT1 receptor antagonist), or their combination was given orally to rats, and their effects were compared on vascular hyperplasia induced by balloon injury. The maximal preventive effect of temocapril and CS-866 alone on neointimal thickening after balloon injury was obtained at a dose of 20 and 10 mg/kg per day, respectively. However, compared with either agent alone, combined temocapril and CS-866 (20 and 10 mg/kg per day, respectively) prevented intimal thickening to a larger extent. Furthermore, compared with either agent alone, combined temocapril and CS-866 prevented vascular smooth muscle cell proliferation in the intima more potently. The increase in platelet-derived growth factor receptor tyrosyl phosphorylation was reduced more potently by the combination of both agents compared with either agent alone. The nonpeptide bradykinin B2 receptor antagonist or the NO synthase inhibitor reduced the prevention of intimal thickening by combined temocapril and CS-866. Compared with either agent alone, the combination of an ACE inhibitor and an AT1 receptor antagonist is more effective in the prevention of vascular hyperplasia due to bradykinin or NO.

Nonpeptide bradykinin B2 receptor antagonists: conversion of rodent-selective bradyzide analogues into potent, orally-active human bradykinin B2 receptor antagonists.

The 1-(2-nitrophenyl)thiosemicarbazide (TSC) derivative, (S)-1-[4-(4-benzhydrylthiosemicarbazido)-3-nitrobenzenesulfonyl]pyrrolidine-2-carboxylic acid [2-[(2-dimethylaminoethyl)methylamino]ethyl]amide (bradyzide; (S)-4), was recently disclosed as a novel, potent, orally active nonpeptide bradykinin (BK) B2 receptor antagonist. The compound inhibited the specific binding of [3H]BK to NG108-15 cell membrane preparations (rodent neuroblastoma-glioma) expressing B2 receptors with a K(i) of 0.5 +/- 0.2 nM. Compound (S)-4 also demonstrated oral efficacy against Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in rats with an ED50 value of 0.84 micromol/kg. After we optimized the terminal binding determinants projecting from the TSC framework, we found that it was possible to replace the potentially toxicophoric nitro and divalent sulfur moieties with only a 15-fold loss in binding affinity ((S)-14a). However, bradyzide and its congeners were found to have much lower affinities for cloned human B2 receptors, expressed in Cos-7 cells. The hitherto synthesized TSC series was screened against the human B2 receptor, and the dibenzosuberane (DBS) pharmacophore emerged as the key structural requirement for potency. Incorporation of this group resulted in a series of derivatives ((S)-14d,e and 19b-d) with K(i) ranges of 10.7-176 nM in NG108-15 cells (expressing the rodent B2 receptor) and 0.79-253 nM in Cos-7 cells (expressing the human B2 receptor). There was no evidence of agonist activity with any of the nonpeptides in any of the cell lines tested. In vivo, oral administration of compound 19c reversed FCA-induced and turpentine-induced mechanical hyperalgesia in rodents with ED50 values of 0.027 and 0.32 micromol/kg, respectively. The selectivity profiles of compounds (S)-14f and (S)-14g were also assessed to determine the conformational and/or steric preferences of the double-ring arrangement. The affinity of (S)-14 g for the human B2 receptor suggested that it may be a hydrophobic interaction with the ethane bridge of the DBS moiety that accounts for the increased potency of compounds (S)-14d,e and 19b,c at this receptor, by favoring a binding mode inaccessible to the unsubstituted diphenylmethyl derivative, (S)-4.

Pharmacological Characterization Of Bradykinin B1 and B2 Receptors In IMR‐90 and INT‐407 Human Cell Lines Using A Microphysiometer

1. In the present study, we used a microphysiometer to measure bradykinin-induced acidification responses in IMR-90, a human lung fibroblast cell line, and INT-407, a human colonic epithelial cell line. Furthermore, we investigated the effect of 24 h exposure of transforming growth factor (TGF)-alpha on the bradykinin response in INT-407 cells. 2. Bradykinin (0.1-100 nmol/L) was potent in producing acidification responses in IMR-90 cells (pEC50 8.79+/-0.13; Hill slope 0.96+/-0.04) and INT-407 cells (pEC50 8.90+/-0.04; Hill slope 1.00+/-0.07). These responses were competitively antagonized by the bradykinin B2 receptor antagonist icatibant in both IMR-90 cells (apparent pKB = 8.54+/-0.15; Hill slope = 1.09+/-0.13 and 1.66+/-0.26 in the absence and presence of 10 nmol/L icatibant, respectively) and INT-407 cells (pKB = 8.12+/-0.07 (3, 10 and 30 nmol/L icatibant); Hill slope = 1.06+/-0.04). However, the bradykinin B1 receptor antagonist des-Arg9Leu8-bradykinin (3 micromol/L) had no effect on the bradykinin responses. 3. The non-peptide bradykinin B2 receptor antagonist FR173657 selectively antagonized bradykinin-induced acidification responses in INT-407 cells in a competitive manner (pKB = 8.76+/-0.10; Hill slope = 0.92+/-0.05) at lower concentrations (1 and 3 nmol/L) but in an insurmountable manner at higher concentrations (10 nmol/L; Hill slope = 1.04+/-0.09). This compound, at concentrations of 10 and 100 nmol/L (Hill slope = 1.38+/-0.15), also proved to be an insurmountable antagonist in IMR-90 cells. 4. The bradykinin B1 receptor selective agonist Lys0des-Arg10-bradykinin (0.1 nmol/L to 0.1 micromol/L) failed to produce acidification responses in IMR-90 cells, even after 24 h pre-incubation with bacterial lipopolysaccharide (0.1 microg/mL). 5. A 24 h pre-incubation of INT-407 cells with TGF-alpha (1, 10 and 100 ng/mL) caused a significant concentration-dependent decrease in maximal bradykinin response without affecting the pEC50. 6. In addition to this study being the first to use a microphysiometer to characterize bradykinin B2 receptors in cultured IMR-90 human lung fibroblast cells and INT-407 human colonic epithelial cells, we also showed that pre-incubation of INT-407 cells with TGF-alpha caused a significant decrease in maximal acidification response mediated by bradykinin B2 receptors.

New conformationally homogeneous beta-turn antagonists of the human B2 kinin receptor.

We have designed and synthesized a conformationally homogeneous series of cyclic pentapeptides of the general structure c[Pro-aa(i)-D-Tic-Oic-aa(i + 3)] which adopt a type-II' beta-turn conformation believed important for high affinity antagonism of the bradykinin (BK) B2 receptor. We incorporated D-Tic and octahydroindole-2-carboxylic acid (Oic) residues (present in known active antagonists) in a cyclic pentapeptide that would place the D-aa in the i + 1 position of the beta-turn and a proline as a bridge between the C- and N-termini sides of the turn. In positions i and i + 3 alkyl, aromatic, polar or charged amino acids could be introduced without dramatically changing the overall structure. Ten analogues were studied using 1H nuclear magnetic resonance (NMR) and evaluated for their binding affinity for the human B2 receptor. The NMR data in dimethylsulfoxide (DMSO) confirmed the structural homogeneity within the class and, on the basis of this, one representative member of the series was chosen for a detailed structure determination using NMR data in sodium dodecylsulphate (SDS) micelles and molecular dynamics calculations. Despite the structural similarity, the binding affinity of the ten analogues was strongly influenced by the nature of the side-chains in positions i and i + 3, with the doubly charged analogue 49 (pKi = 6.2) proving best. This compound may serve as the starting point for the discovery of new non-peptide bradykinin B2 receptor antagonists.

Novel non-peptide lead structures for bradykinin B2-receptor antagonists

A series of new non-peptide Bradykinin (BK) B2-receptor antagonists is reported. These new leads belong to a larger set including both commercially or otherwise available potential candidates found by proprietary database searches using 3D-pharmacophore models as query, and several bis-benzamidino compounds selected from our tryptase-like protease inhibitor library on the basis of topological considerations, derived from the same models. Some of these compounds show functional competitive antagonistic activity, inhibiting in vitro the BK-induced contraction of isolated guinea-pig ileum (GPI) and rat uterus with a pA2 up to 5.3 and 7.0, respectively. They display also binding affinity (IC50 up to 0.56 μM) to the BK B2-receptor in radioligand binding assays on GPI membrane preparations and on human IMR-90 fetal lung fibroblast cells expressing this receptor subtype. Furthermore, the results with the commercially available compounds, in some cases developed as therapeutics, show that the used 3D-pharmacophore model allows to predict to some certainty possible side actions of potential drugs.

Intrinsic prostacyclin contributes to exudation induced by bradykinin or carrageenin: A study on the paw edema induced in IP-Receptor-deficient mice

To prove that prostaglandin I 2 (PGI 2) is a major prostaglandin involved in bradykinin-induced exudation, we examined carrageenin- or bradykinin-induced paw edema in prostacyclin receptor-deficient mice (IPKO). Paw volume of wild-type mice (IPWT) increased gradually 5–6 hr after the carrageenin injection in a similar manner as in ICR mice, but the swelling in IPKO mice was significantly smaller (about 60% of the IPWT volume). Indomethacin, at 10 mg/kg, suppressed the swelling of the IPWT paw to the level of the non-pretreated IPKO, which was not affected by indomethacin, confirming the previous result that PGI 2 is a major prostaglandin involved in the swelling. The paw edema of IPWT and IPKO was significantly attenuated by the non-peptide bradykinin B2-receptor antagonist FR173657, at 30 mg/kg, to the same level of swelling, indicating kinin involvement. Injection of bradykinin (1.2 nmole) into the paw caused rapid edema, which peaked around 15 min in both mice. However, the edema induced in IPKO was smaller and almost at the same level as that elicited in the indomethacin-treated IPWT, suggesting that edema induced by bradykinin includes the intrinsic effect of PGI 2. Concomitant injection of carbacyclin with bradykinin caused enhancement of edema in IPWT mice but not in IPKO mice, indicating that intrinsic PGI 2 could cause enhancement of bradykinin- or even carrageenin-induced edema formation. These results clearly demonstrate that bradykinin released by carrageenin may be a key mediator to induce PGI 2 formation, and both autacoids work together to induce enhanced inflammatory exudation.

ChemInform Abstract: Design and Synthesis of a Novel Class of Highly Potent Selective and Orally Active Non‐peptide Bradykinin B2 Receptor Antagonists

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

LF16-0687 a novel non-peptide bradykinin B2 receptor antagonist reduces vasogenic brain edema from a focal lesion in rats.

Head injury world wide is still the most frequent cause of morbidity and mortality among the population under 45 years. Approximately 50% of patients dying from severe head injury have a therapy refractory intracranial pressure rise (Baethmann 1998). Traumatic brain edema, e.g. resulting from disruption of the blood-brain barrier is viewed as an important factor of the increased intracranial pressure. Bradykinin, an active peptide of the kallikrein-kinin system is considered to enhance brain edema formation which is attributed to its permeabilizing effect on the blood-brain barrier and on dilation of arterial blood vessels in the brain mediated by B2-receptors facilitating extravasation. Currently, LF16-0687, a novel non-peptide bradykinin B2 receptor antagonist was experimentally tested as to its therapeutical potential on vasogenic brain edema from a cortical focal lesion. Following trephination of the skull in anaesthesia, male Sprague-Dawley rats were subjected to a focal cold injury of the left parietal cortex. Animals of two experimental groups were receiving either LF16-0687 as high or low dose, whereas one group of untreated animals with trauma was treated with 0.9% NaCl as continuous infusion beginning 10 min before until 24 h after lesion. 24 h after trauma the brain was removed from the skull, and the cerebral hemispheres were separated in the median plane for gravimetric assessment of hemispheric swelling. No significant reduction of hemispheric brain swelling (+7.4 +/- 2.9%) was found in animals receiving high-dose LF16-0687 as compared to the untreated controls. Brain swelling, however was significantly attenuated by the low-dose treatment, i.e. to +6.4 +/- 1.3%; vs. +9.3 +/- 1.1% found in the controls, (p < 0.05). The current data confirm that blocking of bradykinin B2-receptors by LF16-0687 is significantly attenuating vasogenic brain edema from a focal cold lesion. The therapeutical properties of the antagonist on brain edema formation cannot be attributed to a lowering of the blood pressure. Rather, specific blocking effects of B2-receptors in the brain appear to be involved. In conclusion, the understanding of secondary brain damage including brain edema in head injury has been markedly enhanced by the discovery of pathophysiologically active mediator compounds playing a role in its various manifestations. The current data confirm a pathophysiological function of bradykinin in vasogenic brain edema mediated by activation of B2-receptors. Currently it is studied whether LF16-0687 also reduces brain swelling when given after an insult.

903 LF 16.0687, a new nonpeptide bradykinin B2 receptor antagonist, reduces cerebral edema in a rat model of closed head trauma

Shapira, Y. MD PhD**; Pruneau, D. PhD*; Artu, A. MD#; Chorny, I. MD**; Benkoviz, V. MD**; Talmor, D. MD**; Roytblat, L MD** Author Information

Discovery of orally active nonpeptide bradykinin B2 receptor antagonists

Orally active nonpeptide bradykinin (BK) B2 receptor antagonists have been discovered by using directed random screening and chemical modification. These compounds displaced [3H]BK binding to B2 receptors in guinea-pig ileum membranes, rat uterus membranes and human lung fibroblasts with nanomolar IC50s. They did not inhibit different specific radio-ligand bindings to other receptor sites including B1 receptors. In isolated guinea-pig ileum preparations, these compounds had no agonistic effect on smooth muscle contraction at 10−6 M, and caused parallel rightward shifts of the concentration–response curves to BK on contraction with higher pA2 values. They also blocked human B2 receptor-mediated phosphatidylinositol hydrolysis without agonistic effect. In vivo, the oral administrations of these antagonists potently inhibited BK-induced bronchoconstriction in guinea-pigs. They also reduced carrageenin-induced paw edema and caerulein-induced pancreatitis in rats. Moreover, these compounds alleviated kaolin-induced pain in mice by oral administration. These results show that our compounds are potent, selective, and orally active BK B2 receptor antagonists and that they may have therapeutic potential against inflammatory diseases and pain.

Oral antinociception and oedema inhibition produced by NPC 18884, a non-peptidic bradykinin B2 receptor antagonist.

This study investigates the antinociceptive and the oedema inhibition properties of the novel non-peptide bradykinin (BK) B2 receptor antagonist, NPC 18884. Given by i.p. or p.o. routes NPC 18884 produced graded and long-lasting (at least 2.5h and 5.0h, respectively, for i.p. and p.o. administration) inhibition of acetic acid-induced abdominal constrictions in mice, with mean ID50 values of 8.3 nmol/kg and 439.9 nmol/kg. NPC 18884 also inhibited kaolin-induced abdominal constrictions (44+/-9% and 48+/-3% of inhibition, for i.p. and p.o. routes, respectively). Given by i.p. or p.o. routes NPC 18884 attenuated both phases of formalin-induced licking, as well as formalin-induced oedema formation. At similar doses NPC 18884 produced significant inhibition of capsaicin-induced nociception. NPC 18884, like HOE 140 given i.p., prevented the nociception caused by BK with mean ID50 values of 0.85 nmol/kg and 0.44 nmol/kg, respectively. Given orally NPC 18884, but not HOE 140, caused graded inhibition of BK-induced nociception (mean ID50 value of 50 nmol/kg). In rats, NPC 18884 given i.p. prevented BK and carrageenan-induced hyperalgesia (mean ID50 values of 6 nmol/kg and 13 nmol/kg), without affecting the hyperalgesia induced by des-Arg9-bradykinin (DABK) or by prostaglandin E2 (PGE2). NPC 18884 given i.p. inhibited the mouse paw oedema induced by tyrosine8-bradykinin or by carrageenan, but had no effect on DABK-induced oedema in mice pre-treated with Escherichia coli endotoxin, or that induced by PGE2. Thus, the novel non-peptide BK B2 receptor antagonist NPC 18884 produces rapid onset, potent and relatively long-lasting oral antinociceptive and oedema inhibition properties. The anti-BK actions of NPC 18884 are quite selective towards the BK B2 receptor-mediated responses.

ChemInform Abstract: A Novel Class of Orally Active Non‐Peptide Bradykinin B2 Receptor Antagonists. Part 2. Overcoming the Species Difference Between Guinea Pig and Man.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

In vitro and in vivo effects of the new nonpeptide bradykinin B2 receptor antagonist, LF 16-0335C, on guinea-pig and rat kinin receptors.

Activation of the kinin-kallikrein system and stimulation of bradykinin (BK) B2 receptors are thought to play an important role in the pathophysiology of inflammation and pain. In the present study, we report the pharmacological properties of a novel nonpeptide bradykinin B2 receptor antagonist, LF 16-0335C, (1-[[3-[(2,4-dimethylquinolin-8-yl) oxymethyl]-2,4-dichloro-phenyl]sulfonyl]-2(S)-[[4-[4- (aminoiminomethyl)-phenylcarbonyl]piperazin-1-yl]carbo nyl]pyrrolidine, 2HCl). In binding studies, LF 16-0335C competed with [3H]bradykinin giving Ki values of 1.65 +/- 0.36 nM and 2.20 +/- 0.30 nM in membrane preparations from rat uterus (RU) and guinea-pig ileum (GPI), respectively. In functional experiments, LF 16-0335C inhibited in a competitive manner BK-induced contractions of both isolated RU and GPI, leading to calculated pA2 values of 7.70 +/- 0.70 and 8.30 +/- 0.30, respectively. The inhibitory effect of LF 16-0335C was fully reversible by washing in the guinea-pig ileum. In vivo, LF 16-0335C given intravenously inhibited in a dose-dependent manner BK-induced hypotension in both animal species, although it was more potent in the guinea-pig than in the rat (ED50, 2.5 +/- 1.6 micrograms/kg versus 22.6 +/- 2.3 micrograms/kg). BK is a potent constrictor of guinea-pig airways and this effect was markedly attenuated by LF 16-0335C. In contrast, LF 16-0335C did not affect histamine- and acetylcholine-induced hypotensive response in the rat. We conclude that LF 16-0335C is a potent and selective nonpeptide B2 receptor antagonist which equally binds to the rat and guinea-pig receptor but displays a different in vivo potency in the two species. Therefore, this drug represents a useful tool to better assess the role of bradykinin in pathophysiological conditions.

Design and synthesis of a novel class of highly potent, selective and orally active nonpeptide bradykinin B2 receptor antagonist

Design and synthesis of a novel class of highly potent, selective and orally active nonpeptide bradykinin B2 receptor antagonist