Non-peptide ligands for bradykinin receptors 1995 – 2004

Abstract

It has been a decade since the area of bradykinin (BK) research was last reviewed in this journal. Within this period of time, selective, high-affinity non-peptide BK ligands have been identified by different research groups for both the B₁ and B₂ receptors (B₁R and B₂R). The efficacies of these agents in animal models of human diseases suggest that it may be possible to develop such compounds into novel classes of therapeutic drugs. The emerging pharmacological evidence from these studies suggests that B₁R and B₂R antagonists may be clinically useful for the treatment of pain, inflammation, cancer, hypotension, asthma, colitis, rhinitis, pancreatitis, sepsis and rheumatoid arthritis. B₂R agonists, on the other hand, may alleviate cardiovascular disorders, such as congestive heart failure, hypertension and ischaemic heart disease, and are potentially useful for the treatment of diabetic disorders by mimicking the beneficial effects of BK on glucose uptake and insulin sensitivity. A major challenge in targeting the B₂R is maintaining a balance between the opposing beneficial (cardioprotective, anti-inflammatory) and debilitating (pro-inflammatory, cardiocompromising) effects upon activation or inhibition of this receptor subtype. For this reason, the last few years have seen a significant shift in research emphasis to the B₁R subtype due to its disease-dependent expression. This review will focus on the advances in BK medicinal chemistry reported between 1995 and the beginning of December 2004, with particular emphasis on small-molecule patent disclosures made during this period.

Keywords::

• B₁
• B₂
• bradykinin
• bradykinin receptor agonist
• bradykinin receptor antagonist
• cancer
• inflammation
• kallidin
• non-peptide
• pain