Discovery of orally active nonpeptide bradykinin B2 receptor antagonists

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Abstract

Orally active nonpeptide bradykinin (BK) B2 receptor antagonists have been discovered by using directed random screening and chemical modification. These compounds displaced [3H]BK binding to B2 receptors in guinea-pig ileum membranes, rat uterus membranes and human lung fibroblasts with nanomolar IC50s. They did not inhibit different specific radio-ligand bindings to other receptor sites including B1 receptors. In isolated guinea-pig ileum preparations, these compounds had no agonistic effect on smooth muscle contraction at 10−6 M, and caused parallel rightward shifts of the concentration–response curves to BK on contraction with higher pA2 values. They also blocked human B2 receptor-mediated phosphatidylinositol hydrolysis without agonistic effect. In vivo, the oral administrations of these antagonists potently inhibited BK-induced bronchoconstriction in guinea-pigs. They also reduced carrageenin-induced paw edema and caerulein-induced pancreatitis in rats. Moreover, these compounds alleviated kaolin-induced pain in mice by oral administration. These results show that our compounds are potent, selective, and orally active BK B2 receptor antagonists and that they may have therapeutic potential against inflammatory diseases and pain.

Introduction

Bradykinin (BK), an endogenous nonapeptide produced by kallikrein, has various biological actions such as bronchoconstriction, plasma extravasation, release of prostaglandins/leukotrienes, smooth muscle contraction/relaxation and nociception (Burch et al., 1990; Bhoola et al., 1992). Therefore, BK has potentially important roles in inflammatory diseases such as asthma, rhinitis, arthritis, and pancreatitis. To investigate the pathophysiological role of BK and to develop a drug for inflammatory diseases, a number of BK antagonists have been synthesized (Burch et al., 1990; Stewart, 1995; Regoli et al., 1998). Recently, so-called `second-generation' B2 antagonists, such as Icatibant and Bradycor, have been reported (Hock et al., 1991; Wirth et al., 1991; Cheronis et al., 1992). These compounds have higher affinity for B2 receptors and longer lifetimes than previous B2 antagonists. However, they are all peptide analogs and their therapeutic use is limited because of their poor oral bioavailability. Some nonpeptide B2 antagonists have already been discovered (Sawutz et al., 1994), but they are neither potent nor orally active. Therefore, we tried to find a potent and orally active nonpeptide B2 receptor antagonist by using directed random screening and chemical modification.

Section snippets

Finding a lead compound

We found the lead compound for nonpeptide B2 receptor antagonists by a unique process (Abe et al., 1998). In general, it is very difficult to get a good lead compound. However, we took notice of the relationship between BK and angiotensin. Angiotensin II is a typical vasoconstrictor, whereas BK causes vasodilation. They seem to play key roles in regulating cardiovascular homeostasis through their specific G-protein-coupled receptors.

Angiotensin-converting enzyme generates angiotensin II from an

Potent and orally active nonpeptide B2 antagonists

We obtained potent and orally active B2 receptor antagonists by chemical modifications (Fig. 2) (Asano et al., 1997b, Asano et al., 1998; Inamura et al., 1997). First, we found FR167344 (Fig. 2a) from the dichloro-benzyloxy-imidazopyridine structure. A methyl group at the 2-position is very important for the binding to B2 receptors, and the incorporation of halogen at the 3-position remarkably increases B2 binding activity. As a next step, we tried to find the replacement of the imidazopyridine

Effects of nonpeptide B2 antagonists on animal models of inflammation

We have examined effects of nonpeptide B2 antagonists on animal models of inflammation to study their therapeutic potential against inflammatory diseases (Asano et al., 1997a). Our data reveal that FR167344 and other nonpeptide antagonists have the inhibitory effects on paw edema, pain reaction, and pancreatitis models.

Fig. 3a shows the effect of FR167344 on the carrageenin-induced rat paw edema. The carrageenin injection provoked edema time-dependently, and the oral administration of the

Conclusions

We have discovered orally active nonpeptide BK B2 receptor antagonists by a directed random screening process and chemical modification. The antagonists specifically inhibited BK-induced responses both in vitro and in vivo. They also had inhibitory effects on several in vivo animal models of inflammation. These results indicate that our nonpeptide BK B2 receptor antagonists may have therapeutic potentials against inflammatory diseases. We hope that our nonpeptide antagonists will not only be

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