Novel Subtype-Selective Nonpeptide Bradykinin Receptor Antagonists FR167344 and FR173657

Abstract

We describe the receptor binding and antagonistic properties of two novel nonpeptide antagonists, FR167344 (3-bromo-8-[2,6-dichloro-3-[N-[(E)-4-(N,N-dimethylcarbamoyl)cinnamido acetyl]-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine hydrochloride) and FR173657 (8-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-m ethylamino]-2,6-dichlorobenzyloxy]-2-methylquinoline), for the human bradykinin receptor subtypes (B1 and B2). In competitive experiments using membranes prepared from Chinese hamster ovary cells expressing the bradykinin receptor subtypes, FR167344 and FR173657 showed a high affinity binding to the B2 receptor with IC50 values of 65 and 8.9 nM, respectively, and no binding affinity for the B1 receptor. FR167344 and FR173657 inhibited the B2 receptor-mediated phosphatidylinositol (PI) hydrolysis and produced a concentration-dependent rightward shift in the dose-response curve to bradykinin. This shift was accompanied by a progressive reduction of maximal response. Estimated pA2 values for the antagonism of bradykinin-induced PI hydrolysis by FR167344 and FR173657 were 8.0 and 9.0, respectively. FR167344 and FR173657 showed no stimulatory effects on PI hydrolysis. Therefore, FR167344 and FR173657 are potent, highly selective, and insurmountable antagonists for the human bradykinin B2 receptor.

International Union of Pharmacology. XLV. Classification of the Kinin Receptor Family: from Molecular Mechanisms to Pathophysiological Consequences

“…Subsequently, researchers at Fujisawa described new structurally distinct nonpeptide B 2 receptor antagonists (Aramori et al, 1997b;Abe et al, 1998b), such as FR173657 ( Fig. 2) with substantially higher B 2 receptor affinity and demonstrated selectivity versus the B 1 receptor.…”

The Kallikrein-Kinin System: Current and Future Pharmacological Targets

“…The peptidase-resistant B1R agonist Sar-[DPhe 8 ]des-Arg 9 -BK has been used to further stimulate the formation of compensatory vasculature in a rodent ischemia model after occlusion of the femoral artery (281). FR190997 is a nonpeptide B2R agonist (or partial agonist) derived chemically from a series of B2R antagonists (282). Speculatively, it has been proposed that this drug could be exploited as an antihypertensive or cardioprotective agent, but clinical testing remains to be performed (283).…”

Effects of a nonpeptide bradykinin B2 receptor antagonist, FR167344, on different in vivo animal models of inflammation

“…We have previously described a novel, potent, selective, orally active and long acting nonpeptide bradykinin B 2 receptor antagonist, FR167344 (N-[N-[3-[(3-bromo-2- Figure 1) (Aramori et al, 1997;Inamura et al, 1997 . Moreover this compound potently antagonized bradykinin-induced contractions with a pA 2 value of 9.3 in guinea-pig isolated ileum, but it did not inhibit [des-Arg 9 ]-bradykinin-induced rabbit aorta contractions (mediated by B 1 receptors) or acetylcholine or histamine-induced guinea-pig ileum contractions even at 10 76 M .…”