Bradykinin B2 receptor antagonists

Bas M. Bier H. Greve J, Kojda G, Hoffmann T Novel pharmacotherapy of acute hereditary angioedema with bradykinin B2-receptor antagonist icatibant. Allergy 2006 61 1490-1492. 

In rats, ramipril reduced renal lithium clearance and increased fractional lithium reabsorption in association with decreased systolic blood pressure and decreased sodium excretion. These effects were attenuated by icati-bant, a specific bradykinin B2 receptor antagonist (577). 

Lorenzl S, Kodel U, Frei K, Pfister HW (1996) Effect of the bradykinin B2 receptor antagonist Hoel40 in experimental pneumococcal meningitis in the rat. Eur J Pharmacol 308 335-341 Lumenta DB, Plesnila N, Klasner B, Baethmann A, Pruneau D, Schmid-Elsaesser R, Zausinger S (2006) Neuroprotective effects of a postischemic treatment with a bradykinin B2 receptor antagonist in a rat model of temporary focal cerebral ischemia. Brain Res 1069 227-234 Mac Donald CL, Dikranian K, Bayly P, Holtzman D, Brody D (2(X)7) Diffusion tensor imaging reliably detects experimental traumatic axonal injury and indicates approximate time of injury. J Neurosci 27 11869-11876... 

Indications Hereditary angioedema (HAE) in adults Category Bradykinin B2 receptor antagonist Half-life 1-2 hours... 

Abe et al. reported that the imidazol [l,2-a]pyridine moiety of the basic framework of a class of the non-peptide bradykinin B2 receptor antagonists (11, Figure 15.14) could be successfully replaced by several heterocyclic bioisosteres. Among those, the l-methyl-2-methoxy-l//-benzimidazole, 2-methylquinoxaline and 2-methylquinoline derivatives showed potent B2 binding affinities against both human and guinea pig B2 receptors (Figure 15.14). 

Pineda LF, Liebmann C, Hensellek S, Paegelow I, Steinmetzer T, Schweinitz A, Stiirze-becher J, Reissmann S. Novel non-peptide lead structures for bradykinin B2-receptor antagonists. Lett Pept Sci 2000 7 69-77. 

To evaluate the contribution of bradykinin B2-receptor-mediated mechanisms, the selective bradykinin B2-receptor antagonist, HOE-140, is given to ganglion-blocked, the rats are captopril treated, and the increases in SBP, DBP, heart rate, and plasma adrenaline/noradrenaline induced by test peptide and bradykinin (group GB-i-Cap-i-HOE) are observed. To evaluate the contribution of ATl-receptor-mediated mechanisms, the selective ATI receptor antagonist, losartan, is given to group GB rats before and after treatment with captopril (1 mg/kg, i.v.) and the increases in SBP, DBP, heart rate, and plasma adrenaline/noradrenaline induced by test peptide are observed. 

FIGURE 15.14 Novel class of orally active non-peptide bradykinin B2 receptor antagonists showing valuable examples of imidazo[l,2-a]pytidine analogs. 

Electron-rich isoxazoles are also known to undergo electrophilic substitution under similar conditions. The bromination of 5-aminoisoxazole provided the 4-bromo derivative that was utilized as part of a synthesis of a library of compounds screened for their ability to act as bradykinin B2 receptor antagonists. ... 

Access to Negishi Precursors. 2-Lithio-l-methylimidazole can also be transmetalated to their zincated analogs for use in Negishi-t)q)e couplings to access targets such as bradykinin B2 receptor antagonists. The utility of these reagents is illustrated in the scale-up of AG-28262 (eq 26). ... 

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