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WO1998007746A1 - Antagonistes du recepteur de la bradykinine b1 et leur utilisation - Google Patents

Antagonistes du recepteur de la bradykinine b1 et leur utilisation Download PDF

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Publication number
WO1998007746A1
WO1998007746A1 PCT/CA1997/000582 CA9700582W WO9807746A1 WO 1998007746 A1 WO1998007746 A1 WO 1998007746A1 CA 9700582 W CA9700582 W CA 9700582W WO 9807746 A1 WO9807746 A1 WO 9807746A1
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desarg
bradykinin
receptor
leu
arg
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PCT/CA1997/000582
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English (en)
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Domenico Regoli
Gérard E. PLANTE
Fernand Gobeil
Witold A. Neugebauer
Adriana Zuccollo
Orlando L. Catanzaro
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Universite De Sherbrooke
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Priority to US09/242,751 priority Critical patent/US7041785B1/en
Priority to AU39358/97A priority patent/AU3935897A/en
Publication of WO1998007746A1 publication Critical patent/WO1998007746A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/18—Kallidins; Bradykinins; Related peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to B ⁇ antagonists that have a good affinity and selectivity for a B receptor; a subset thereof at least partially resistant to enzymatic degradation.
  • B BK bradykinin
  • B receptors are formed de novo and take part in the induction and/or the maintenance of pathological states. Or, as pointed out by Marceau 6 , "it is conceivable that B, receptors can amplify the responses of injured tissues to kinins and, in some cases, take the relay of B 2 receptors in chronic pathologies". B, receptor antagonists have been discovered in the late seventies 7,8 but no substantial progress has been made in this area, despite the evidence of their usefulness in basic pharmacology and in various experimental pathologies. We already demonstrated that capillary permeability was augmented in streptozocin (STZ) diabetic rat model 49 .
  • STZ streptozocin
  • the vascular BK receptors of the portal veins of these animals have been shown to present enhanced contractibility and capillary permeability in response to B agonist desArg 9 BK, when compared to normal animals. This effect was abolished by B ⁇ antagonist Lys[Leu ⁇ ]desArg 9 BK while the B 2 -antagonist HOE140 had no effect thereon. A similar increased sensitivity to desArg 9 BK was observed in untreated SHR animals, prior to the establishment of hypertension, which was reversed by the same B ⁇ antagonist.
  • B receptor is a target for a drug-preventive approach to diabetic or hypertensive vasculopathy
  • clinical testing becomes possible in as much as B antagonists capable of resisting to a very rapid enzymatic degradation are obtained.
  • Substitutions in the natural B.- agonist desArg 9 -BK at amino acid residue proline have provided antagonists resistant to ACE degradation 23 .
  • Further protection against amino peptidases is provided by adding non-hydrolysable amino acid residues at the N-terminal end.
  • modifications at both residue 7 and N-terminal end also resulted in a loss of affinity for B,-receptor and even showed antagonistic activity towards B 2 -receptor.
  • bradykinin antagonists also exist: D-Arg[Hyp 3 ,Thi 5 ,D- Tic 7 ,Oic 8 ]desArg 9 BK (S0765), [Hyp 3 ,Thi 5 ,D-Tic 7 ,Oic 8 ]desArg 9 BK (S1629) both developed by Hoechst, D-Arg[Hyp 3 ,D-Hyp 7 (transpropyl),Oic 8 ]desArg 9 BK (NPC18565) and D-Arg[Hyp 3 ,D-Hyp 7 (trans thiophenyl), Oic 8 ]desArg 9 BK (NPC18828), both developed by Scios Inc., are antagonists completely resistant to ACE degradation. However, none of them are selective for B ⁇ receptor when tested in model tissues.
  • compositions comprising these Brantagonists and a pharmaceutically acceptable carrier are also an object of the invention.
  • a condition is particularly an inflammatory condition, more particularly a diabetic vasculopathy, other diabetic symptoms associated with an insulitis or a post-capillary resistance consequent to the presence of a B receptor.
  • Novel B r BK receptor antagonists are provided. These antagonists are selective to B r BK receptors, and some of them are partially or totally resistant to enzymatic degradation.
  • bradykinin BK
  • KD kallidin
  • LysBK and BK are agonists of B 2 -receptors, normally present at the membrane surface of numerous cells.
  • C-terminal truncated metabolites [Lys]desArg 9 BK and desArg 9 BK are agonists of a B r receptor, not present on normal cells, but synthesized de novo during inflammation.
  • Brantagonists of the present invention are peptide analogs of desArg 9 BK.
  • the present invention is the result of a study that was undertaken to search for new peptidic B, receptor antagonists, starting with the most active known structure Lys[Leu 8 ]desArg 9 BK 5 and trying to improve it. Changes were made at the N-terminal end to find the most suitable group that maintains affinity and protects from degradation by aminopeptidases and in positions 7 and 8 to improve affinity and resistance to kininase II or ACE (EC 3.4.15.1), the enzyme that plays a major role in the inactivation of the kinins and their desArg 9 -metabolites 8 9 . New compounds were prepared and tested in several isolated organs to provide precise pharmacologic profiles and assess affinity and selectivity for the B, receptor.
  • Figures 1a), 1 b) and 1c) represent the effect of HOE140 (a selective B 2 bradykinin receptor antagonist) on glycemia, proteinuria and kallikrein excretion, respectively, in control mice and streptozotocin-induced diabetes type I in mice.
  • HOE140 a selective B 2 bradykinin receptor antagonist
  • Figures 2a), 2b) and 2c) represent the effect of [Leu 8 ]desArg 9 BK (a selective B bradykinin receptor antagonist) on glycemia, proteinuria and kallikrein excretion, respectively, in control mice and streptozotocin-induced diabetes type I in mice.
  • [Leu 8 ]desArg 9 BK a selective B bradykinin receptor antagonist
  • Tissues were taken from New Zealand white rabbits (1.5-2.5 kg) and Dunken Hartley guinea pigs (250-350 g) of either sex, killed by stunning and exsanguination.
  • Umbilical cords were taken from healthy women 22-40 years old after spontaneous delivery at term.
  • the rabbit jugular vein (RbJV), the guinea pig ileum (GPI), two preparations containing B 2 receptors, the rabbit aorta (RbA) (B 1 receptor) and the human umbilical vein (HUV), a mixed preparation containing both B, and B 2 receptors 10 were used.
  • Helical strips of RbJV treated with 1 ⁇ mol/L of captopril to avoid peptide degradation by the angiotensin-converting enzyme (ACE), alias kininase II were prepared according to Gaudreau et a/. 11
  • Helical strips of RbA devoid of endothelium were prepared according to Furchgott and Bhadrakom 12 .
  • Longitudinal segments of GPI were prepared with the procedure described by Rang 13 .
  • Helical strips of HUV were prepared according to Gobeil et a/. 10 .
  • the tissues were suspended in 10-ml organ baths containing warm (37°C), oxygenated (95% O 2 -5% CO 2 ) Krebs solution of the following composition in mmol/L; NaCI: 118.1 ; KCI: 4.7; CaCI 2 6H 2 O: 2.5; KH 2 PO 4 : 1.2; MgSO 4 7H 2 O: 1.18; NaHCO 3 : 25.0 and D-Glucose: 5.5.
  • the RbA and the HUV were stretched with an initial tension of 2 g, whereas the RbJV and the GPI were loaded with 0.5 g. Changes of tension produced by the various agents were measured with Grass isometric transducers (model FT 03C, Grass Instrument Co., Quincy, Mass.). Myotropic contractions were displayed on a Grass polygraph (model 7D). Before testing the drugs, the tissues were allowed to equilibrate for 60-120 min during which time the tissues were repeatedly washed and the tension readjusted every 15 min.
  • bradykinin (BK) (9 nmol/L) was applied repeatedly on the RbJV, the GPI or the HUV to ensure that tissues responded with stable contractions.
  • BK bradykinin
  • the B preparation whose response has been shown to increase during the incubation in vitro 7
  • desArg 9 BK (550 nmol/L) was applied 1 ,3 and 6 h after the equilibration period, in order to monitor the progressive increase of sensitivity of the tissue which generally reaches the maximum after 3-6 h.
  • a similar protocol was used for the HUV.
  • HUV a mixed B ⁇ and B 2 receptor preparation
  • HOE140 400 nmol/L
  • Lys[Leu8]des Arg 9 BK (1 ⁇ mol/L) a potent B, receptor antagonist
  • All kinin antagonists were initially applied to tissues at concentration of 10 ⁇ g/mL to measure their potential agonistic activities ( ⁇ E ) in comparison with BK (in the B 2 receptor preparations) or desArg 9 BK (in the B. receptor preparations).
  • ACE angiotensin-converting enzyme
  • the B 2 antagonist D-Arg[Hyp 3 , Thi 5 , D Tic 7 , Oic 8 ]BK (HOE140), and HOE140 derivatives (D-Arg[Hyp 3 , Thi 5 , D-Tic 7 , Oic 8 ]desArg 9 BK (S 0765) and [Hyp 3 , Thi 5 , D-Tic 7 , Oic 8 ]desArg 9 BK) (S 1629)) 17 were given by Dr. B.
  • Hyp trans-4-hydroxy-L-proline
  • Thi p-(2-thienyl)L-alanine
  • Tic L- (1 ,2,3,4-tetrahydroisoquinoline-3carboxylic acid
  • Oic L-(3aS, 7aS)-octahydro-indol-2-carboxylic acid
  • ⁇ Nal ⁇ -3-(2-naphthyl) alanine: Sar: sarcosine (N-methyl-glycine); eAhx: e-aminohexanoicacid.
  • Captopril was purchased from Squibb Canada (Montreal, Canada).
  • the results obtained with three series of compounds designed to a) improve antagonistic affinity, b) eliminate residual agonistic activities and c) prevent the degradation of B, receptor antagonists by ACE, are presented in Table 1 , 2 and 3.
  • the first series (Table 1) includes compounds (containing a Hyp residue in position 3), which may derive from the conversion by carboxypeptidases of classical B 2 receptor antagonists into C-terminal desArg ragments.
  • the results, summarized in Table 1 present the pharmacological profile of each compound in terms of affinities (pA 2 ) for the B, receptor (RbA) and affinities (if any), as well as residual agonistic activities on two B 2 receptor subtypes (RbJV, GPI). Percent of degradation (after 30 min of incubation) by ACE is also indicated.
  • D-Arg[D-Tic 7 , He 8 ]desArg 9 BK is an antagonist on the B, receptor showing a pA 2 value of 6.97 with no agonistic activity on the B 2 receptor and negligible degradation by ACE.
  • Replacement of the D-Tic stereoisomer (compound 14) in position 7 causes a diminution of the antagonistic potency (pA 2 ⁇ 5.04) on the B, receptor as well as regaining its susceptibility of being metabolized by ACE.
  • the same results have been obtained when the D-Tic residue in position 7 has been replaced by a smaller residue such as an Ala (see compound 15).
  • the presence of a Hyp residue in position 3 does not seem to play any particular role (see compounds 16, 17).
  • HOE140 (10 ⁇ g/mL), and thus, should be considered as non specific.
  • Leu has the advantage over lie in eliminating partial agonistic activities on the GPI (and RJV) as well as conferring better protection against ACE hydrolysis (see Table 3). However, this latter substitution causes a slight reduction of antagonism potency compared to those containing an He (see Table 3).
  • the AcLys[D- ⁇ Nal 7 ,lle 8 ]desArg 9 BK (compound 19) represents the most potent B 1 receptor antagonist (pA 2 8.40 ⁇ 0.12) with little residual agonistic effect on the GPI ( ⁇ E 0.38) and is partially metabolized by ACE in our experimental conditions.
  • the four compounds maintain high affinity for the B, receptors of the RbA (pA 2 values of 8.10 to 8.5) and little, if any, residual agonistic activities on the B 2 receptors of the RbJV and the GPI. They are however broken down by ACE, especially those (compounds 27, 28) which do not possess D-amino acid in position 7.
  • B, and B 2 receptor antagonists containing Oic in position 8 are presented in Table 4. These compounds, prepared by investigators at Hoechst and Scios were tested in the same assays as those of Tables 1 , 2 and 3. All compounds exhibit complete resistance to ACE metabolism. All compounds are devoid of partial agonistic activity on both B, and B 2 receptor preparations. The presence of a D-residue in position 7 and of Oic in position 8 appear to be essential inasmuch for metabolic protection than for inactivity as agonists. All compounds presented in Table 4 are non selective and represent a new class of antagonists which are able to block both B, and B 2 receptors.
  • the stereospecificity of the residue ⁇ Nal in position 7 is again crucial, likewise in the rabbit, since the isomeric form L- ⁇ Nal shows 3 orders of magnitude less antagonistic activity than the D- ⁇ Nal form.
  • Two of the compounds designed for labelling through an elongation of the N-terminal show very high affinities for the human B receptor and are inactive on the human B 2 receptor. These results are similar to what have been observed on the rabbit B, receptor.
  • the Hoechst compound (S 0765) is a pure B, receptor antagonist (pA 2 7.29) which is in contrast with its mixed B, and B 2 antagonistic activities on the rabbit tissues.
  • the NPC 18828 behaves as an antagonist on both human B, and B 2 receptors with a marked predominance for the former. Worthy of notice is the overall resemblance in the pharmacological profiles of the human and the rabbit B, receptors described in the present study. Discussion
  • the present analysis concerns four series of peptides designed to improve B, receptor antagonism and obtain compounds with high affinity, full selectivity for the B, receptor and resistance to degradation by ACE and possibly aminopeptidases. To these goals, substitutions were made in positions 3, 7 and 8 of [Leu B ]desArg 9 BK and one residue or more were added to the N-terminal end, since Lys[Leu 8 ]desArg 9 BK has been shown to be at least 10 times more active than [Leu 8 ]desArg 9 BK in the rabbit 78 and the human 1025 .
  • the first series of compounds was therefore designed to evaluate the role of Hyp 3 and the results presented in Table 1 indicate that the Hyp in position 3 does not influence the antagonist affinities in the rabbit B receptor.
  • kallidin and desArg 10 -kallidin are sensitive to aminopeptidases (e.g. Aminopeptidase M; EC 3.4.11.2) and can be protected by N-acetylation 5 .
  • First and second generation of antagonists have however a D-Arg at the N-terminal, a substitution which has also been shown to protect against degradation by aminopeptidases (see Stewart and Vavrek) 31 .
  • D- ⁇ Nal in position 7 not only protects (quite efficiently) from degradation by ACE, but confers higher affinity (by three log units) and selectivity for the rabbit and human B, receptors.
  • the only limitation of compound 19 is its residual agonistic activity on the GPI, which appears to be due to a contractile effect of unknown nature, since it is not antagonized either by HOE140 (a ⁇ -2 receptor antagonist), or by Losartan (a AT, receptor antagonist), indomethacin (a cyclooxygenase inhibitor) and atropine (a muscarinic receptor antagonist) (data not shown).
  • D-Tic residue because of its rigid and cyclic structure may exert a greater influence on peptide conformation than the D- ⁇ Nal residue which has its side chain more flexible.
  • both residues because of their hydrophobic nature and their opposite stereochemical configuration may enable the accessibility on the receptor via a hydrophobic pouch.
  • the non radioactive iodinated peptide (compound 30) was synthesized in order to assess possible changes in affinity and enzymatic resistance of this latter peptide. No significant changes were seen on the pharmacological and biochemical properties of compound 29, thus the SarTyreAhxLys[D- ⁇ Nal 7 , lle 8 ]desArg 9 BK (compound 29) may have its usefulness in binding studies on the kinin B, receptors.
  • Oic a non-aromatic tryptophan-like derivative
  • D-stereoorientation aminoacid in position 7 conjointly with a D-stereoorientation aminoacid in position 7, have been shown to possess important effects such as preservation of B 2 receptor antagonism, at least on the rabbit B 2 receptor subtype, and thus provides a new category of antagonists acting on both B 1 and B 2 receptors.
  • the D-Arg[Hyp 3 , Thi 5 , D-Tic 7 , Oic '-desArg BK (S 0765) and the D-Arg[Hyp , D-'Tic (tr ns thiophenyl), Oic 8 ]desArg 9 BK (NPC 18828) have shown dissimilarity between human and rabbit B 2 receptor antagonism (see Tables 4 and 5). This may be explained by the existence of heterogenous bradykinin B 2 receptors between species and/or tissues. Furthermore, this is supported by previous studies which have demonstrated that the S 0765 compound shows differential antagonistic potency between species 34 * 35 .
  • the S 0765 compound is a poor B 2 receptor antagonist in humans (present study), rats 35 and guinea pigs 34 35 (present study) whereas it shows high potency in rabbit tissues 35 (present study).
  • NPC 18828 is a very active and quite selective antagonist of the human B, receptor, and interacts with the rabbit but not with the guinea pig B 2 receptor subtype (Table 4).
  • the present structure-activity study has therefore provided indications on the stereochemical requirements that might contribute to high potency and selectivity for B 1 receptor antagonism. From the results presented above, it appears that the chemical features favouring affinity of antagonists on the human B, receptor are similar to those for the rabbit B, receptor, as already emphasized by Regoli et a/. 36 and Gobeil et a/. 10 .
  • Capillary permeability is known to be selectively augmented in the streptozotocin (STZ) diabetic rat model 49 .
  • STZ streptozotocin
  • the vascular BK receptors in the STZ-induced diabetic rat was examined. Segments of the portal vein (a known preparation for BK studies) from these rats were mounted in organ baths for isometric contraction studies.
  • the response to desArg 9 BK, a specific BK-B, receptor agonist was enhanced by 118% in the diabetic tissue, compared to normal portal veins (0.48 vs 0.22g: P ⁇ 0.001). This enhanced sensitivity was abolished by Lys[Leu 8 ]desArg 9 BK, a specific antagonist of the BK-B 1 receptor.
  • HOE140 the BK-B2 receptor antagonist
  • HOE140 the BK-B2 receptor antagonist
  • Example 1 the Brantagonists described in Example 1 , particularly those that are proteolysis- resistant, are now suitable for a drug-preventive approach to diabetic vasculopathy, by targeting B receptor without being extensively degraded prior to reaching this receptor.
  • HYPERGLYCEMIA DIURESIS, PROTEINURIA, NITRITE AND KALLIKREIN URINARY EXCRETION ARE ALL NORMALIZED BY B r BK RECEPTOR BLOCKADE: Streptozotocin has been extensively used to produce type I diabetes in animals.
  • kinins have been proposed as prominent inflammatory mediators in the pathogenesis of several diseases, we evaluated the role of kinins and their receptors in the evolution of insulitis.
  • Male C57BL/Ks mdb mice were injected with streptozotocin (40 mg/kg) for 5 consecutive days.
  • the kinin B, receptor antagonist [Leu 8 ]desArg 9 BK or the B 2 antagonist HOE140 were injected subcutaneously to STZ mice at 300 ug/Kg bw twice a day and 500 ug/Kg per day, respectively. Treatment with antagonists was started 3 days after STZ and lasted for 10 days.
  • Plasma glucose was determined by the glucose oxidase method, and 13 days urinary samples were assayed for proteins, nitrites and kallikreins.
  • Diabetic mice showed hyperglycemia and increased diuresis, marked proteinuria and increased excretion of nitrites and kallikreins.
  • the treatment with B 2 receptor antagonist did not show any effect on glycemia, but it reduced significantly water and protein excretion, compared to STZ group.
  • STZ mice treated with B, receptor antagonist showed normal glycemia and complete normalization of diuresis, protein, nitrite and kallikrein excretion.
  • the results obtained in the investigation support the assumption that the kallikrein kinin system intervenes in the maintenance of diabetic lesions and also indicates that B, kinin receptors play the most significant role in this experimental disease.
  • the animals were housed at a constant room temperature, with a 12 h light-dark cycle.
  • Animals were randomly divided into the following groups: A: control treated with solvent. B: treated with streptozotocin (STZ), 40 mg/kg, during 5 consecutive days C: treated with STZ + B., antagonist: 3 days after the beginning of the treatment with STZ, the animals were injected twice a day with the B., receptor antagonist [Leu 8 ]desArg 9 BK (300 ug/kg) subcutaneously for 10 days D: treated with STZ + B 2 antagonist: 3 day after treatment with STZ, the animals received D-Arg[Hyp 3 ' Thi 5 , D Tic 7 , Oic 8 ]BK (HOE140) 500 ug/Kg/day subcutaneously during 10 days.
  • A control treated with solvent.
  • B treated with streptozotocin (STZ), 40 mg/kg, during 5 consecutive days
  • C treated with STZ + B., antagonist: 3 days after the beginning of the treatment with STZ, the animals were injected twice a day with the B., receptor antagonist [Leu 8 ]
  • Streptozotocin was purchased from the Sigma Chem Co., St. Louis, Mo. It was dissolved in 0.02 M citrate buffer pH, 4.5 and immediately injected intraperitoneally.
  • [Leu 8 ]desArg 9 BK was purchased from Sigma Chem Co., and HOE140 was kindly provided by Dr. B. Sch ⁇ lkens from HOECHST, Frankfurt, Germany.
  • Kallikrein assay was performed using synthetic chromogenic substrate H-D-Val-Leu-Arg-pNA(S-2266) from Kabi, Sweden. The paranitroanilide (pNA) released by enzymatic action on the substrate was measured colorimetrically to determine kallikrein activity Statistical analysis
  • Fig. 1 The results obtained in the groups of animals used to evaluate the role of B 2 receptors are presented in Fig. 1.
  • the effect of HOE140 in control and diabetic mice was evaluated by measuring body weight, glycemia and renal functions, particularly urinary volume, proteinuria, kallikrein and nitrites urinary excretion. No changes of body weight were observed between the various groups of mice.
  • the two groups treated with STZ showed a significant increase of blood glucose: the treatment with B 2 receptor antagonist did not show any effect on glycemia.
  • Diabetic mice (STZ) showed increased diuresis, marked proteinuria, as well as increased excretion of nitrites and kallikreins.
  • HOE140 the diabetic animals showed significant reduction in the renal functions, compared to the STZ group.
  • Urinary volume was however reduced only by half and still remained significantly elevated with respect to controls; the same was found to be true for protein and nitrite excretion. Kallikrein excretion was brought back to normal by the treatment with HOE140. Effects of the B, receptor antagonist. [Leu 8 ]desArg 9 BK.
  • mice used to evaluate the effects of B, receptor antagonist are summarized in Figure 2.
  • Body weight was similar in all groups STZ treated mice showed significant increase of glycemia, urinary volume, as well as protein, nitrite and kallikrein excretion, similar to those of the group analysed in Fig. 1.
  • STZ mice treated with the B, receptor antagonist showed normal glycemia, thus indicating that blockage of B 1 receptors is associated with a normalization of the blood glucose.
  • Treatment with the B, antagonist was effective also in preventing the increase of the urinary volume, as well as those of protein, nitrite and kallikrein in the urine, that is normally observed in diabetic mice. Discussion
  • Streptozotocin-induced diabetes in the mouse is associated with an inflammatory reaction 38 of the Langerhans islets 46 with incremented production of NO 37 and with modifications of renal functions.
  • the results obtained in the present investigation support entirely our assumption and also indicate that the kinin receptor that plays the most significant role may be the B This conclusion is based on the observation that prolonged (10 days) treatment with [ Leu 8 ]desArg 9 BK is associated with a correction of the biochemical parameters that characterize STZ-induced diabetes. Blood glucose of STZ + B, antagonist group was normal, indicating that B.
  • Block of B 2 receptors does not lead to correction of glycemia, supporting the interpretation that insulitis is a slowly developing inflammatory reaction, primarily mediated by B, receptors.
  • B 2 receptors may play a role at the kidney level, in the glomerular membrane, where their activation may lead to increase of permeability. This mechanism is invoked to explain the partial correction of diuresis, proteinuria and the total correction of kallikrein which was found in the HOE140 treated mice.
  • Desendothelialized portal vein segments obtained from SHR were mounted in organ baths containing a Krebs solution supplemented with captopril (3uM), for isometric contraction studies (baseline tension: 0.5 g).
  • the selective B BK agonist, des-Arg 9 -BK was administered on portal vein segments obtained from normal rats and SHR, to establish dose-response curves to DesArg 9 BK, from 10 9 to 10 '5 M.
  • Example 2 it is contemplated that the preferred Brantagonists described in Example 1 can be advantageously used in replacement of Lys[Leu 8 ]desArgBK.
  • compounds 8, 9, 12, 13, 17 to 19, and 23 to 30, which appear to be at least 2 to 5 times less susceptible to ACE proteolytic degradation may be dosed to achieve an effect equivalent to the one observed in vivo in STZ-mice with a dosage regimen of 300 ⁇ g/Kg b.i.d. subcutaneously (see Example 3).
  • the doses of the novel B antagonists need to be adjusted to take into account the pharmacokinetic and pharmacodynamic principles well known in the art: mode of administration, absorption, distribution, clearance, effective dose, side effects, etc.
  • the antagonists of the present invention are the first to be usable for conducting more extensive clinical studies, since they combine acceptable affinity, selectivity and, in some instances, resistance to degradation.
  • Rb.A. (rabbit aorta); Rb.J.V. (rabbit jugular vein); G.P.I, (guinea pig ileum); n.d. (not determined).
  • pA 2 - Log 10 of the molar concentration of the antagonist required to reduce the effect of a double concentration of agonist to a single one.
  • pD 2 indicating apparent affinity as an agonist, n.d.: not determined; F.ag.: full agonist; P.ag.: partial agonist.
  • HOE 140 a new potent and long-acting bradykinin antagonist: in vitro studies. Brit. J. Pharmacol. 1991 ;102:769-773.
  • Rhaleb NE Gobeil F
  • Regoli D Non-selectivity of new bradykinin antagonists for B, receptor. Life Sci. 1992;51 :125-129.

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Abstract

L'invention concerne de nouveaux antagonistes d'un récepteur de la bradykinine B1 (B1-BK), qui ont une bonne affinité et une bonne sélectivité pour ledit récepteur et dont certains sont au moins partiellement résistants à la dégradation enzymatique. La synthèse des récepteurs B1 est induite par l'inflammation. Les symptômes associés à l'inflammation (pression hydrostatique élevée et fuite ou extravasation plasmatique) ont été observés chez les modèles animaux diabétiques (diabète induit par la streptozotocine (STZ)) ainsi que chez les rats spontanément hypertendus (SHR). Les présents inventeurs confirment la présence de récepteurs B1-BK chez ces deux modèles. Les antagonistes B1-BK ont aboli la vasoconstriction induite par la B1-BK chez les STZ et les SHR, et abaissé la glycémie des animaux diabétiques jusqu'à la ramener à un taux normal. Ces antagonistes B1 sont utiles pour traiter tous les états dans lesquels le récepteur B1 est exprimé, notamment durant l'inflammation, et plus particulièrement les états dans lesquels l'expression dudit récepteur entraîne une vasculopathie diabétique, d'autres symptômes diabétiques associés à une insulite et l'installation d'une résistance post-capillaire due à la présence d'un récepteur B1.
PCT/CA1997/000582 1996-08-19 1997-08-14 Antagonistes du recepteur de la bradykinine b1 et leur utilisation WO1998007746A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005042027A2 (fr) 2003-10-22 2005-05-12 Amgen Inc. Antagonistes du recepteur de la bradykinine b1
WO2006017938A1 (fr) * 2004-08-19 2006-02-23 UNIVERSITé DE SHERBROOKE Nouveaux antagonistes peptidiques et peptidoïdes du récepteur de la bradykinine b1 et utilisations de ceux-ci
US7211566B2 (en) 2003-04-01 2007-05-01 Universite De Sherbrooke Selective bradykinin (BK) B1 peptidic receptor antagonists and uses thereof
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Cited By (13)

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US7211566B2 (en) 2003-04-01 2007-05-01 Universite De Sherbrooke Selective bradykinin (BK) B1 peptidic receptor antagonists and uses thereof
US8288351B2 (en) 2003-10-22 2012-10-16 Amgen Inc. Antagonists of the bradykinin B1 receptor
US7605120B2 (en) 2003-10-22 2009-10-20 Amgen Inc. Antagonists of the brandykinin B1 receptor
US8278280B2 (en) 2003-10-22 2012-10-02 Amgen Inc. Antagonists of the bradykinin B1 receptor
WO2005042027A2 (fr) 2003-10-22 2005-05-12 Amgen Inc. Antagonistes du recepteur de la bradykinine b1
WO2006017938A1 (fr) * 2004-08-19 2006-02-23 UNIVERSITé DE SHERBROOKE Nouveaux antagonistes peptidiques et peptidoïdes du récepteur de la bradykinine b1 et utilisations de ceux-ci
US7932228B2 (en) 2004-08-19 2011-04-26 Societe de Commercialisation des Produits de la Recherche Applique Socpra Sciences Sante et Humaines S.E.C. Method of treating bone or prostate cancer with selective bradykinin B1 receptor antagonists
WO2014040192A1 (fr) * 2012-09-13 2014-03-20 British Columbia Cancer Agency Branch Compositions ciblant le récepteur b1 de la bradykinine pour l'imagerie médicale du cancer et d'autres troubles
EP2895204A4 (fr) * 2012-09-13 2016-07-13 British Columbia Cancer Agency Compositions ciblant le récepteur b1 de la bradykinine pour l'imagerie médicale du cancer et d'autres troubles
US10039846B2 (en) 2012-09-13 2018-08-07 British Columbia Cancer Agency Branch Compositions targeting bradykinin receptor B1 for medical imaging of cancer and other disorders
WO2014207534A3 (fr) * 2013-06-25 2015-04-09 Sépia Pesquisa E Desenvolvimento Modulateurs des récepteurs de la bradykinine et leur utilisation
US9920096B2 (en) 2013-06-25 2018-03-20 Sepia Pesquisa E Desenvolvimento Bradykinin receptor modulators and use thereof
WO2024259525A1 (fr) * 2023-06-19 2024-12-26 Societe De Commercialisation Des Produits De La Recherche Appliquee Socpra Sante Et Humaines, S.E.C. Nanoparticules comprenant du n,n,n-triméthyl chitosane revêtu d'agonistes peptidiques de la kinine b1 ou b2 et/ou des antagonistes peptidiques de la kinine b1 pour l'administration transvasculaire de médicament à travers la barrière hémato-encéphalique

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