Short communication 2′-Hydroxy-fendiline analogues as potent relaxers of isolated arteries James Wilkinson a, ⁎ , Dennis Foretia b , Steven Rossington a , Anthony Heagerty b , John Leonard c , Nigel Hussain d , Clare Austin b a Centre for Drug Design, Biosciences Research Institute, Cockcroft Building, University of Salford, Salford M5 4WT, UK b Cardiovascular Research Group, Division of Cardiovascular and Endocrine Sciences, Core Technology Facility, 46 Grafton Street, University of Manchester, M13 9NT, UK c AstraZeneca Process R+D, Silk Road, Macclesfield, Cheshire SK10 2NG, UK d GlaxoSmithKline Chemical Development, Old Powder Mills, Tonbridge, Kent TN11 9AN, UK Received 13 September 2006; received in revised form 8 January 2007; accepted 12 January 2007 Available online 1 February 2007 Abstract Novel, 2′-hydroxy derivatives of fendiline have been synthesised and their ability to induce relaxation of isolated rat small mesenteric and coronary arteries were determined. Both derivatives examined were significantly more potent as vasodilators than fendiline itself. Similar effects were observed on both mesenteric and coronary arteries. © 2007 Elsevier B.V. All rights reserved. Keywords: Fendiline analogues; Isolated arteries; Relaxation 1. Introduction Cardiovascular disorders represent a major cause of mortality and morbidity in the developed world. Despite a considerable number of therapeutic strategies available, the search continues for more potent and efficacious drugs which act on the resistance vasculature to lower blood pressure. Fendiline (S-1 and R-1, Fig. 1) is a diphenylmethane derivative which exhibits both anti-anginal and anti-hyperten- sive properties, effects which are attributed largely to its dilatory effects on small blood vessels (Bayer and Mannhold, 1987). These dilatory effects have been classically attributed to the well documented effects of the drug as an inhibitor of smooth muscle L-type Ca 2+ channels (Tripathi et al., 1993; Nawrath et al., 1998) and/or as a calmodulin antagonist (Johnson et al., 1982; Bayer and Mannhold, 1987). The chemical structures of both Ca 2+ and calmodulin antagonists are somewhat diverse and it is difficult to predict activity based purely on structure (Mannhold et al., 1993; Opie, 1987). As such the search for new, more potent vasodilatory agents relies heavily on the synthesis of new compounds, often derivatives of known vasodilators, and the systematic testing of these in physiological systems. We have recently developed an effective and versatile method for lateral lithiation and alkylation of substituted diarylmethane systems (Wilkinson et al., 2004a,b,c, 2006). This has allowed the synthesis of 2′-substituted analogues of fendiline including those where hydrogen is replaced with a hydroxy group. These analogues have not previously been reported. The aim of the present study is thus to investigate whether this substitution influences the dilatory potency of the compounds. This was examined using isolated small arteries mounted on a wire myograph with effects on contractility being assessed as changes in isometric tension. As these derivatives may have potential as both anti-anginal and anti-hypertensive agents, responses on isolated coronary and mesenteric small arteries were examined and compared. 2. Materials and methods 2.1. Synthetic chemistry The 2'-hydroxy compounds 2 and 3 were synthesised from the known starting material 4 (Fig. 1) by the following methodology which we have previously described (Rossington, European Journal of Pharmacology 561 (2007) 160 – 163 www.elsevier.com/locate/ejphar ⁎ Corresponding author. Tel.: +44 161 295 4046; fax: +44 161 295 5111. E-mail address: j.a.wilkinson@salford.ac.uk (J. Wilkinson). 0014-2999/$ - see front matter © 2007 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2007.01.039