Eotaxin receptor (CCR3) antagonism in asthma and allergic disease.
A range of low molecular weight chemicals have been developed to antagonise the eotaxin receptor, cysteine-cysteine chemokine receptor-3 (CCR3), with the aim of selectively inhibiting eosinophil recruitment into tissue sites. However, the results of recent clinical trials with monoclonal antibodies directed against interleukin-5 (IL-5) question the role of eosinophils in mediating the symptoms of asthma and allergic disease. For this reason, the plans for clinical development of certain CCR3 antagonists have been halted. However, eotaxin 1-3 and a variety of other chemokines interact with CCR3; and this receptor is expressed not only on eosinophils but also on basophils, mast cell subpopulations, activated Th2 cells, macrophages, and airway epithelial cells. Hence, CCR3 is closely associated with asthma and allergy and blockade of this receptor may have pronounced beneficial effects in these diseases. We consider the chemical structures of CCR3 antagonist molecules from a range of pharmaceutical companies, and present an early clinical development plan for a hypothetical CCR3 antagonist. CCR3 antagonists are likely to be safe and effective therapies for allergic diseases, and their clinical pharmacology can readily be defined within phase I/II studies in patients with allergy and asthma.
Erin
E M
EM
NHLI Clinical Studies Unit, Imperial College, London, UK.
Williams
T J
TJ
Barnes
P J
PJ
Hansel
T T
TT
D000818:Animals; D018926:Anti-Allergic Agents / Q000737:chemistry / Q000494:pharmacology*; D018927:Anti-Asthmatic Agents / Q000737:chemistry / Q000494:pharmacology*; D001249:Asthma / Q000188:drug therapy*; D054413:Chemokine CCL11; D018925:Chemokines / Q000502:physiology; D019742:Chemokines, CC / Q000502:physiology; D006801:Humans; D006967:Hypersensitivity / Q000188:drug therapy*; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors* / Q000737:chemistry
D018926:Anti-Allergic Agents; D018927:Anti-Asthmatic Agents; C515456:CCL11 protein, human; C515350:CCR3 protein, human; D054413:Chemokine CCL11; D018925:Chemokines; D019742:Chemokines, CC; D054397:Receptors, CCR3; D019707:Receptors, Chemokine