1. ¹AstraZeneca, Alderley Park, Macclesfield, Cheshire SK10 4TF, UK
2. ²University of Edinburgh, Western General Hospital, Edinburgh, UK

Correspondence: C Morris, E-mail: Clive.morris@astrazeneca.com

Received 9 February 2005; Revised 24 May 2005; Accepted 24 May 2005.

Abstract

Activation of the endothelin A receptor (ET_A) by endothelin-1 (ET-1) mediates events that regulate mitogenesis, apoptosis, angiogenesis and metastasis in tumours. Specific blockade of ET_A may have anticancer effects, while retaining beneficial endothelin B receptor (ET_B)-mediated effects such as apoptosis and clearance of ET-1. ZD4054 is an orally active, specific ET_A antagonist in clinical development. In receptor-binding studies, ZD4054 specifically bound to ET_A with high affinity; no binding was detected at ET_B. In a randomised placebo-controlled trial in eight healthy volunteers, a single oral dose of ZD4054 reduced forearm vasoconstriction in response to brachial artery infusion of ET-1, thus providing clinical evidence of ET_A blockade. ET_B blockade was assessed in an ascending, single-dose, placebo-controlled trial in 28 volunteers. For all doses of ZD4054, mean plasma ET-1 concentrations measured at 4 and 24 h were within the placebo reference range (a rise in ET-1 would indicate ET_B blockade) and there was no evidence of dose-related changes. These data confirm the specificity of ZD4054 for ET_A, with no activity at ET_B in a clinical or preclinical setting. As a result of this specificity, ZD4054 has the potential to block multiple ET_A-induced pathological processes, while allowing beneficial ET_B-mediated processes to continue, which may, in turn, lead to an effective cancer therapy.