Potential clinical applications of kinin receptor ligands
| Type of Agent | Application | Investigational Status | References |
|---|---|---|---|
| B2 receptor agonists | |||
| Labradimil | Transient opening of the blood-brain barrier (adjuvant to chemotherapy of brain tumors) | Extensive animal studies performed | Emerich et al., 2001 |
| Lys-BK | Additive to vaccines to skew the immune response from humoral (TH2) to cellular responses (TH1) | Hypothesis supported by animal data | Aliberti et al., 2003 |
| FR190997, others | Renal, cardiac protection, and hypertension, via endothelial mediator release | Speculative; unfavorable risk to benefit ratio probable | Heitsch, 2002 |
| B1 receptor agonists | |||
| Sar-[d-Phe8]-des-Arg9-BK | Angiogenesis, vasculogenesis in severe ischemic disease | Speculative; supported by animal data | Emanueli et al., 2002 |
| B2 receptor antagonists | |||
| Icatibant, several others | Inflammatory pain (hyperalgesia) | Abundantly supported by animal studies | Steranka et al., 1988; Perkins et al., 1993; Burgess et al., 2000 |
| Icatibant, others | Inflammatory edema | Supported by many animal studies | Uknis et al., 2002; Samadfam et al., 2000 |
| LF16-0687, deltibant | Brain edema (post-traumatic or secondary to stoke) | Mixed results of a limited clinical trial of deltibant for head trauma; extensive animal data supporting LF16-0687; the later drug is being clinically evaluated for head trauma | Narotam et al., 1998; Kaplanski et al., 2002; Zausigner et al., 2002 |
| Icatibant | Hereditary angioedema | Active in a mouse model (C1 inhibitor gene knockout); Icatibant being clinically evaluated for this indication, as well as for ascites secondary to liver cirrhosis (Jerini AG) | Han et al., 2002 |
| Icatibant | Allergic asthma, rhinitis | Objective and protracted anti-inflammatory effects shown in humans following local application to mucosa | Akbary et al., 1996; Turner et al., 2001 |
| Deltibant | Sepsis | Disappointing results of a clinical trial | Fein et al., 1997 |
| B1 receptor antagonists | |||
| [Leu8]-des-Arg9-BK, others | Inflammatory pain (hyperalgesia); effect may extend to neuropathic pain, wind-up, and viscero-visceral hyper-reflexia | Abundantly supported by animal studies; may be effective during a retarded time window, relative to B2 receptor antagonists | Perkins et al., 1993; Bélichard et al., 2000; Levy and Zochodne, 2000; Pesquero et al., 2000; Jaggar et al., 1998 |
| Lys-[Leu8]-des-Arg9-BK, others | Inflammation | Effects in animal models | Blais et al., 2000; deBlois and Horlick, 2001 |
| Unspecified | Epilepsy | Speculative; based on the epileptogenic effect of the agonist in animal models | Bregola et al., 1999 |
| Des-Arg10-Hoe 140 | Airway allergy | Benefits in a rat model; speculative in humans | Huang et al., 1999; Christiansen et al., 2002 |
| Unspecified | Sepsis | Speculative; based on the counterproductive hemodynamic effect of agonist in LPS-pretreated rabbits | Audet et al., 1997 |
| Promiscuous ligands | |||
| CU201 = B9870 | Cancer | Whereas both antagonists of the B1 and B2 receptors have been proposed or used in a limited manner as experimental antineoplasic agents, CU201 may be more effective in specific tumorigenic cell lines than conventional antagonists | Chan et al., 2002a,b; Stewart et al., 2003 |