Bradykinin B, Receptor Antagonists

FIGURE 15.13 Cyclopropylamino add amide as [4iannacophoric replacement for 2,3-diamin( yridine. AppUcation to the design of novel bradykinin B] receptor antagonist and factor Xa inhibitor. 

Lawson SR, Gabra BH, Nantel F, Battistini B, Sirois P. Effects of a selective bradykinin B1 receptor antagonist on increased plasma extravasation in streptozotocin-induced diabetic rats distinct vasculopathic profile of major key organs. European Journal of Pharmacology 2005, 514, 69-78. 

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... 

Faunce, and D. G. Sawutz, J. Med. Chem., 36, 2583 (1993). Design of Potent Non-Peptide Competitive Antagonists of the Human Bradykinin B, Receptor. 

Lys-[Leu ,desArg bradykinin (Lys-[Leu ,desArg ]BK) is a bradykinin receptor antagonist selective for the B -receptor subtype. 

Gougat, J., Ferrari, B., Sarran, L., Planchenault, C., Poncelet, M., Maruani, J., Alonso, R., Cudennec, A., Tiziano Crod, T, Fabio Guagnini, F., Katalin Urban-Szabo, K., Martinolle, J. R, Soubrie, R, Finance, O., Le Fur, G. SSR240612 [(2R)-2-[((3R>3-(l,3-Benzodioxol-5-yl)-3- [(6-methoxy-2-naphthyl)sulfonyl]amino propanoyl)amino] -3-(4- [2/J,6S)-2,6-dimethylpiperidinyl]methyl phenyl)-/V-isopropyl-/V-methylpropanamide Hydrochloride], a new nonpeptide antagonist of the bradykinin B1 receptor biochemical and pharmacological characterization. J. Pharmacol. Exp. Then 2004, 309, 661-669. 

BRADYKININ AND THE EEFECTS OE ACE INHIBITORS ACE inhibitors are used widely in the treatment of hypertension, and they reduce mortality in patients with diabetic nephropathy, left ventricular dysfunction, previous myocardial infarction, or coronary artery disease. ACE inhibitors block the conversion of Angl to Angll, a potent vasoconstrictor and growth promoter (Figure 24-2) (see Chapter 30). Studies using the specific bradykinin B antagonist HOE-140 demonstrate that bradykinin also contributes to many of the protective effects of ACE inhibitors. The contribution of bradykinin to the effects of ACE inhibitors may result not only from decreased degradation of bradykinin but also from induction of enhanced receptor sensitivity. 

While the potential role of bradykinin antagonists is significant, years of research have not been able to adequately define the type of bradykinin receptor that is responsible for pain and inflammation in humans. A B2 antagonist (HOE140 Icatibant) was evaluated clinically but failed to alleviate acute pain. To date there is no B1 antagonist and a clear clinical candidate for B2 is not on the horizon. Nevertheless, the proven involvement of bradykinin in inflammatory pain renders an antagonist of the relevant B-receptor a worthwhile target... 

Chakravarty, S., Mavunkel, B.J., Goehring, R.R. and Kyle, D.J., Novel bradykinin receptor antagonists from a structurally directed non-peptide combinatorial library, Im-munopharm., 33 (1996) 61-67. 

Bork K. Frank J, Grundt B, Schlattmann P. Nussberger J. Kreuz W Treatment of acute edema attacks in hereditary angioedema with a bradykinin receptor-2 antagonist (icatibant). J Allergy Clin Immunol 2007 119 1497-1503. 

---