Bradyzide, a potent non‐peptide B₂ bradykinin receptor antagonist with long‐lasting oral activity in animal models of inflammatory hyperalgesia

Abstract

1 Bradyzide is from a novel class of rodent-selective non-peptide B 2 bradykinin antagonists (1-(2-Nitrophenyl)thiosemicarbazides). 7 Bradyzide is orally available and blocks bradykinin-induced hypotension and plasma extravasation. 8 Bradyzide shows long-lasting oral activity in rodent models of in¯ammatory hyperalgesia, reversing Freund's complete adjuvant (FCA)-induced mechanical hyperalgesia in the rat knee joint (ED 50 , 0.84 mmol kg 71 ; duration of action 44 h). It is equipotent with morphine and diclofenac, and 1000 times more potent than paracetamol, its maximal eect exceeding that of the non-steroidal anti-in¯ammatory drugs (NSAIDs). Bradyzide does not exhibit tolerance when administered over 6 days. 9 In summary, bradyzide is a potent, orally active, antagonist of the B 2 bradykinin receptor, with selectivity for the rodent over the human receptor.

Role of G protein-coupled receptors in inflammation

“…At the periphery, a number of GPCR agonists produced during inflammation, including bradykinin (BK) and selected prostaglandins (PGs), participate in inflammatory hyperalgesia. BK and kallidin both activate and sensitize [35] . Prostaglandins (PGs) are lipid-derived autacoids generated through the sequential actions of cyclooxygenase and PG synthase.…”

The Kallikrein-Kinin System: Current and Future Pharmacological Targets

“…A number of animal models of inflammatory pain have been exploited to show that B1R or B2R antagonists exert analgesia (151). Although the interest for a B1R antagonist is currently strong, due to their efficacy in the later of persistent phases of inflammatory pain, the analgesic effect of recent nonpeptide antagonists of the B2R is surprisingly good (LF 16-0687, bradyzide) (291,292). However, the fact that peptide antagonists of either receptor subtype are analgesic may support a peripheral mode of action, as these agents are likely to be excluded from the CNS.…”

A Novel Nonpeptide Antagonist of the Kinin B1Receptor: Effects at the Rabbit Receptor

“…This affinity surpasses that of the alternate nonpeptide B 1 R antagonist SSR240612 by about 1 log unit in the rabbit aorta contractility assay (pA 2 of 9.4; Gougat et al, 2004); on the other hand, the latter drug is more potent at rodent B 1 Rs than compound 11 (Su et al, 2003), illustrating again the species-specific pharmacological divergences observed for a number of kinin receptor antagonists (Marceau et al, 1998;Burgess et al, 2000). Compound 11 is active as an apparently surmountable antagonist of des-Arg 9 -BK or Lys-des-Arg 9 -BK in the rabbit aorta, but the Schild regression slope is significantly inferior to 1, a finding usually interpreted as lack of competitive behavior.…”

“…These compounds are, respectively, a peptide B 1 R antagonist , a peptide, and a nonpeptide B 2 R antagonist . The nonpeptide B 2 R antagonist bradyzide (Burgess et al, 2000;Dziadulewicz et al, 2000) is a gift from Dr. E. Dziadulewizc (Novartis, London). Losartan, a nonpeptide antagonist of the angiotensin II (Ang II) AT 1 receptor (AT 1 R), and compound 11 (2-{(…”

“…Several nonpeptide antagonists of the parent BK B 2 R have been discovered over the last decade (Pruneau et al, 1999;Dziadulewicz et al, 2000Dziadulewicz et al, , 2002 with proposed applications in inflammatory pain and the prevention of vasogenic edema of the brain (Burgess et al, 2000;Kaplanski et al, 2002;Zausinger et al, 2002). One of the first reported nonpeptide antagonist of the human B 1 R, compound 11 (Fig.…”