8-Aryl Xanthines Potent Inhibitors of Phosphodiesterase 5 Ruth Arnold, a David Beer, a Gurdip Bhalay, a Urs Baettig, a Stephen P. Collingwood, a, * Sarah Craig, a Nicholas Devereux, a Andrew Dunstan, a Angela Glen, a Sylvie Gomez, a Sandra Haberthuer, a Trevor Howe, a Stephen Jelfs, a Heinz Moser, a Reto Naef, b Paul Nicklin, a David Sandham, a Rowan Stringer, a Katharine Turner, a Simon Watson a and Mauro Zurini b a Novartis Horsham Research Centre, Wimblehurst Road, Horsham, West Sussex RH12 5AB, UK b Novartis Pharma AG, Lichtstrasse 35, CH-4056 Basel, Switzerland Received 22 April 2002; revised 23 May 2002; accepted 18 June 2002 Abstract—In clinical studies, several inhibitors of phosphodiesterase 5 (PDE5) have demonstrated utility in the treatment of erectile dysfunction. We describe herein a series of 8-aryl xanthine derivatives which function as potent PDE5 inhibitors with, in many cases, high levels of selectivity versus other PDE isoforms. # 2002 Elsevier Science Ltd. All rights reserved. Inhibition of phosphodiesterase 5 (PDE5) is a clinically proven concept for treatment of male erectile dysfunc- tion (MED), with the PDE5 inhibitor sildenafil 1 laun- ched in 1998, and great recent interest in the development of new PDE5 inhibitors. 1,2 Despite the clear utility of 1, adverse effects such as headaches, flushing and visual disturbance have been noted in a small number of MED patients taking silde- nafil, 3 some of which could be associated with cross reactivity on other PDE isoforms. Competitive inhibi- tion of PDE6, which controls function of rod and cone cells within the eye, may be responsible for some of the ocular side effects observed. 4 In this communication, we disclose the discovery of novel xanthine-based PDE5 inhibitors which exhibit good levels of in vitro potency and differing selectivity over other PDE isoforms, including PDE6. 3-Isobutyl-1-methylxanthine (IBMX) 2a has been long known as a general, non-selective PDE inhibitor. 5 More recently, Corbin 6 described a series of 8-substituted derivatives of IBMX such as 2b and 2c, which exhibited low nM potency against PDE5 and modest selectivity against PDE1. In searching for a selective PDE5 inhi- bitor, one strategy we employed involved a comparative investigation of the similarity of xanthine templates related to 2 and known PDE5 inhibitors such as silde- nafil 1. The absolute binding conformations of these molecules are unknown, and therefore it was sought to determine those common features of known PDE5 inhibitors which were most likely to give rise to their activity at this receptor. Using Catalyst #7 in hip-hop mode, common features in 3-D space were identified and aligned. This confirmed manual attempts at over- laying our compounds where the 6 membered ring of the pyrazolopyrimidine template was overlaid with the five-membered ring of the xanthine template (Fig. 1). The similarities between these two templates promp- ted the design and subsequent synthesis of novel hybrid 3a. 0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(02)00480-8 Bioorganic & Medicinal Chemistry Letters 12 (2002) 2587–2590 *Corresponding author. E-mail: steve.collingwood@pharma.novartis. com