Non-peptide bradykinin B2 receptor

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). 

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

Meini S, Cucchi P, BeUucci F, et al. Site-directed mutagenesis at the human B2 receptor and molecular modelling to define the pharmacophore of non-peptide bradykinin receptor antagonists. Biochem Pharmacol 2004 67 601-9. 

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. 

Like angiotensin 11, non-peptide B2 receptor antagonists and agonists of bradykinin were obtained by random screening approaches. Chemical modifications on random screening leads like 101 led to non-peptide antagonists... 

Bradykinin-related peptides are potent vasoactive molecules implicated in inflammation and pain that mediate their acute actions via two receptors one inductible (Bl) and the other expressed (B2). It appears that a Bl-selective antagoifist would be useful as anti-inflammatory agents. The majority of non-peptidic Bl antagoifists have a basic amine and a lipophilic sulfonamide as exemplified by compound 1 (SR240612, A" = 0.48 nM), the distance between the basic nitrogen and the sulfonamide has been recognized as cracial for binding selectivity to the Bl subtype over the B2. Lead... 

---