HOE 140

Icatibant(HOE-140) is a selective and specific antagonist of bradykinin B2 receptor with IC50 and Ki of 1.07 nM and 0.798 nM respectively. IC50 value: 1.07 nM [1] Target: bradykinin B2 receptor antgonist in vitro: In receptor binding studies in guinea-pig ileum preparations, Hoe 140 showed an IC50 of 1.07 x 10(-9) mol l-1 and a KI value of 7.98 x 10(-10) mol l-1. In isolated organ preparations Hoe 140 and D-Arg-[Hyp2,Thi5,8, D-Phe7]BK inhibited bradykinin-induced contractions concentration dependently, with IC50-values in the guinea-pig ileum preparation of 1.1 x 10(-8) mol l-1 and 3 x 10(-5) mol l-1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively [1]. in vivo: HOE 140 (1, 3, or 10 μg/10 μl physiological saline) was administered into the wound by a sterile micropipette. HOE 140 (1, 3, 10 μg) significantly relieved mechanical allodynia and guarding in comparison with vehicle-treated group [2]. HOE-140 (10 nmol/kg) protected against memory impairment. This treatment attenuated the brain edema, interleukin-1β, tumor necrosis factor-α, and nitric oxide metabolites content elicited by mLFPI. Accordingly, HOE-140 administration protected against the increase of nicotinamide adenine dinucleotide phosphate oxidase activity, thiobarbituric-acid-reactive species, protein carbonylation generation, and Na+ K+ ATPase inhibition induced by trauma [3].

References:
[1]. Hock FJ, et al. Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies. Br J Pharmacol. 1991 Mar;102(3):769-73. [2]. George J, et al. Locally Mediated Analgesic Effect of Bradykinin Type 2 Receptor Antagonist HOE 140 During Acute Inflammatory Pain in Rats. J Burn Care Res. 2014 Jan 21. [3]. Ferreira AP, et al. HOE-140, an antagonist of B2 receptor, protects against memory deficits and brain damage induced by moderate lateral fluid percussion injury in mice. Psychopharmacology (Berl). 2014 May;231(9):1935-48.

Therapeutic potential of icatibant (HOE-140, JE-049).[Pubmed:18710362]

Expert Opin Pharmacother. 2008 Sep;9(13):2383-90.

There is now a substantial body of work implicating bradykinin, an endogenous peptide neurohormone, in the pathophysiology of a variety of inflammatory conditions in man. Icatibant (HOE-140, JE-049), a highly selective antagonist at the bradykinin B2 receptor, blocks the vasodilatation and increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man. Recent attention has focused on the therapeutic potential of icatibant in a number of human disease states. The most promising of these is hereditary angioedema in which Phase III clinical trials have recently been completed and regulatory approval is currently being sought in Europe and the USA. A therapeutic role for icatibant has also been proposed in several other human conditions including drug-induced angioedema, airways disease, thermal injury, refractory ascites in patients with liver cirrhosis, and acute pancreatitis, although this work remains largely experimental.

HOE-140, an antagonist of B2 receptor, protects against memory deficits and brain damage induced by moderate lateral fluid percussion injury in mice.[Pubmed:24202114]

Psychopharmacology (Berl). 2014 May;231(9):1935-48.

RATIONALE: There are evidences indicating the role of kinins in pathophysiology of traumatic brain injury, but little is known about their action on memory deficits. OBJECTIVES: Our aim was to establish the role of bradykinin receptors B(1) (B(1)R) and B(2) (B(2)R) on the behavioral, biochemical, and histologic features elicited by moderate lateral fluid percussion injury (mLFPI) in mice. METHODS: The role of kinin B(1) and B(2) receptors in brain damage, neuromotor, and cognitive deficits induced by mLFPI, was evaluated by means of subcutaneous injection of B(2)R antagonist (HOE-140; 1 or 10 nmol/kg) or B(1)R antagonist (des-Arg9-[Leu8]-bradykinin (DAL-Bk; 1 or 10 nmol/kg) 30 min and 24 h after brain injury. Brain damage was evaluated in the cortex, being considered as lesion volume, inflammatory, and oxidative damage. The open field and elevated plus maze tests were performed to exclude the nonspecific effects on object recognition memory test. RESULTS: Our data revealed that HOE-140 (10 nmol/kg) protected against memory impairment. This treatment attenuated the brain edema, interleukin-1beta, tumor necrosis factor-alpha, and nitric oxide metabolites content elicited by mLFPI. Accordingly, HOE-140 administration protected against the increase of nicotinamide adenine dinucleotide phosphate oxidase activity, thiobarbituric-acid-reactive species, protein carbonylation generation, and Na(+) K(+) ATPase inhibition induced by trauma. Histologic analysis showed that HOE-140 reduced lesion volume when analyzed 7 days after brain injury. CONCLUSIONS: This study suggests the involvement of the B(2) receptor in memory deficits and brain damage caused by mLFPI in mice.

Locally mediated analgesic effect of bradykinin type 2 receptor antagonist HOE 140 during acute inflammatory pain in rats.[Pubmed:24451303]

J Burn Care Res. 2014 Nov-Dec;35(6):e391-8.

Opioids like morphine form the mainstay of treatment for moderate to severe burn pain. However, lack of dedicated burn care service and potentially serious side effects of opioids often compromise effective treatment. Newer drugs as well as newer routes of administration of analgesic drugs are long-felt needs in the management of burn pain. Bradykinin is a potent inflammatory mediator present at sites of tissue damage. The present study investigated the analgesic effect of bradykinin type 2 receptor antagonist HOE 140 after direct intrawound administration in rats. Also, whether the analgesic effect was locally mediated was further evaluated. Tissue damage was produced by a surgical incision involving skin, fascia, and muscle. It has been reported that there are minor differences in inflammatory mediators underlying incision-related and burn injury-related pain. HOE 140 (1, 3, or 10 mug/10 mul physiological saline) was administered into the wound by a sterile micropipette. After an interval of 30 seconds, the wound was closed. HOE 140-induced analgesic effect was compared to other experimental groups of rats which did not receive any drug or those which were treated with either saline (vehicle) or water. Postincisional pain was determined by monitoring behavior, allodynia, and thermal hyperalgesia. Analgesic effect was also determined after drug administration in contralateral paw. HOE 140 (1, 3, 10 mug) significantly relieved mechanical allodynia and guarding in comparison with vehicle-treated group. The analgesic effect of HOE 140 was locally mediated. Healing of the wound was normal. In conclusion, the results suggest that bradykinin type 2 receptor antagonists such as HOE 140 could be useful in the treatment of acute inflammatory pain.

Bradykinin Impairs and HOE 140 does not Protect Rat Hindlimb Skeletal Muscle Against Tourniquet-induced Reperfusion Injury.[Pubmed:26375056]

J Invest Surg. 2016;29(1):13-9.

BACKGROUND: Bradykinin (BK) is used in different tissues. Dose-dependent studies have demonstrated that low doses protect against ischemia/reperfusion (I/R) injury while higher doses lead to adverse effects. Although the beneficial effects of BK infusion were observed in myocardium, its role on the I/R impact in skeletal muscle (SM) has not been fully clarified. OBJECTIVE: This study was carried out to evaluate the effects of BK, administered in the hindlimbs of rats subjected to I/R. METHODS: The study design included three experimental groups: Group 1 control (saline), Group 2 (bradykinin), and Group 3 (HOE 140, a BK2 receptor blocker). In all three groups, rats were subjected to hindlimb ischemia for a total of 2 h followed by continuous 4 h of reperfusion with pharmacological interventions. The methods include analysis of enzymes (lactate dehydrogenase-LDH and creatinine phosphokinase-CPK), cell membrane marker of injury (malondialdeyde-MDA), recruitment of neutrophils (myeloperoxidase-MPO), and apoptosis index (immunohistochemistry TUNEL in situ peroxidase dead end). RESULTS: Except for the apoptotic index, all parameters studied were shown to be elevated in the reperfusion group intervened with BK. The blocking of BK2 receptors by HOE 140 did not affect the I/R injury. CONCLUSION: After 2 h of total ischemia, infusion of bradykinin during 4 h of reperfusion, worsened the I/R injury in the hindlimb skeletal muscle.

The bradykinin B2 receptor antagonist icatibant (Hoe 140) blocks aminopeptidase N at micromolar concentrations: off-target alterations of signaling mediated by the bradykinin B1 and angiotensin receptors.[Pubmed:17026984]

Eur J Pharmacol. 2006 Dec 3;551(1-3):108-11.

The N-terminal sequence of icatibant, a widely used peptide antagonist of the bradykinin B(2) receptors, is analogous to that of other known aminopeptidase N inhibitors. Icatibant competitively inhibited the hydrolysis of L-Ala-p-nitroanilide by recombinant aminopeptidase N (K(i) 9.1 microM). In the rabbit aorta, icatibant (10-30 microM) potentiated angiotensin III, but not angiotensin II (contraction mediated by angiotensin AT(1) receptors), and Lys-des-Arg(9)-bradykinin, but not des-Arg(9)-bradykinin (effects mediated by the bradykinin B(1) receptors), consistent with the known susceptibility of these agonists to aminopeptidase N. At concentrations possibly reached in vivo (e.g., in kidneys), icatibant alters physiological systems different from bradykinin B(2) receptors.

Agonistic and antagonistic properties of the bradykinin B2 receptor antagonist, Hoe 140, in isolated blood vessels from different species.[Pubmed:8075888]

Br J Pharmacol. 1994 Jun;112(2):683-9.

1. HOE 140, a recently described bradykinin B2 antagonist, and NPC 567 from an earlier generation of bradykinin B2 antagonists, were tested in rabbit and sheep isolated blood vessels. 2. In rabbit jugular vein, a bradykinin B2 preparation, NPC 567 was an antagonist (apparent pA2: 8.67 +/- 0.16) with marked residual agonistic activity (log[EC50]: -7.29 +/- 0.13). HOE 140 was a potent non-competitive antagonist devoid of agonistic properties (slope of the Schild plot: 2.02; estimated pA2: 9.04). 3. In rabbit aorta, a bradykinin B1 preparation, NPC 567 was a competitive antagonist (pA2: 6.32 +/- 0.13) but HOE 140 was ineffective. The two antagonists did not show any agonistic properties in this tissue. 4. In sheep femoral artery without endothelium, bradykinin and HOE 140 induced contractions with identical efficacy and similar potency (log[EC50]: -8.05 +/- 0.12, -7.73 +/- 0.10; maximal contraction in % of KCl [60 mM]: 59.5 +/- 15.1, 62.0 +/- 13.1; for bradykinin and HOE 140, respectively). In contrast NPC 567 was an extremely weak agonist. The contractile responses to bradykinin and HOE 140 were inhibited by NPC 567 (apparent pKB: 6.89 +/- 0.22 and 6.58 +/- 0.08 versus bradykinin and HOE 140, respectively) but not by a B1 bradykinin antagonist, suggesting that the receptor involved was a bradykinin B2 receptor. 5. In sheep femoral artery with endothelium, bradykinin induced a biphasic response: an endothelium-dependent relaxation and a contraction which were both inhibited by NPC 567 (apparent pKB: 7.10 +/- 0.15) and HOE 140 (pA2: 8.38 +/- 0.12). As bradykinin B2 receptor antagonists, HOE 140 and NPC 567 were less potent in the sheep femoral artery than in the rabbit jugular vein. Neither HOE 140 nor NPC 567 were agonists for the endothelial receptor.6. This study demonstrates that HOE 140, a new bradykinin B2 receptor antagonist, is more selective and more potent than NPC 567; however, it may possess, depending on the tissue studied, marked residual agonistic properties. Furthermore, bradykinin B2 receptors are subject to important species specificity. Finally, two different bradykinin B2 receptor subtypes may coexist in the sheep femoral artery with endothelium.

Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies.[Pubmed:1364851]

Br J Pharmacol. 1991 Mar;102(3):769-73.

1. HOE 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin) is a new bradykinin (BK)-antagonist. It was tested in several in vitro assays and compared with D-Arg-[Hyp2,Thi5,8,D-Phe7]BK. 2. In receptor binding studies in guinea-pig ileum preparations, HOE 140 showed an IC50 of 1.07 x 10(-9) mol l-1 and a KI value of 7.98 x 10(-10) mol l-1. 3. In isolated organ preparations HOE 140 and D-Arg-[Hyp2,Thi5,8, D-Phe7]BK inhibited bradykinin-induced contractions concentration dependently, with IC50-values in the guinea-pig ileum preparation of 1.1 x 10(-8) mol l-1 and 3 x 10(-5) mol l-1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC50 value was 4.9 x 10(-9) mol l-1 for HOE 140. D-Arg-[Hyp2, Thi5,8, D-Phe7]BK showed an IC50 of 4.0 x 10(-6) mol l-1. The IC50 values in the guinea-pig isolated pulmonary artery were 5.4 x 10(-9) mol l-1 and 6.4 x 10(-6) mol l-1, respectively. In the rabbit aorta no inhibitory effects on Des-Arg9-BK induced contractions were observed. 4. In cultured bovine endothelial cells, HOE 140 antagonized (IC50 = 10(-8) mol l-1) bradykinin-induced endothelium-derived relaxing factor (EDRF) release and the bradykinin-induced increase in cytosolic free calcium (IC50 = 10(-9) mol l-1). 5. HOE 140 (10 -7mol I1) totally suppressed the bradykinin-induced (10 8 to 10- mol I') prostacyclin (PGI2) release from cultured endothelial cells of bovine aorta. D-Arg-[Hyp2, Thi5'8, D-Phe7]BK (10- 7 mol I1- ) showed a weaker antagonism. 6. Taken together these results show that HOE 140 is a highly potent bradykinin antagonist. It was two to three orders of magnitude more potent than D-Arg-[Hyp2, Thi5 8, D-Phe7]BK.

Icatibant (HOE-140) is a selective and specific antagonist of bradykinin B2 receptor with IC50 and Ki of 1.07 nM and 0.798 nM respectively.

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