Design and Synthesis of Xanthine Analogues as Potent and Selective PDE5 Inhibitors Yuguang Wang,* Samuel Chackalamannil, Zhiyong Hu, Craig D. Boyle, Claire M. Lankin, Yan Xia, Ruo Xu, Theodros Asberom, Dmitri Pissarnitski, Andrew W. Stamford, William J. Greenlee, Jeffrey Skell, Stanley Kurowski, Subbarao Vemulapalli, Jairam Palamanda, Madhu Chintala, Ping Wu, Joyce Myers and Peng Wang Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA Received 11 June 2002; accepted 25 July 2002 Abstract—We have discovered potent and selective xanthine PDE5 inhibitors. Compound 25 (PDE5 IC 50 =0.6 nM, PDE6/ PDE5=101) demonstrated similar functional efficacy and PK profile to Sildenafil (PDE5 IC 50 =3.5 nM, PDE6/PDE5=7). # 2002 Elsevier Science Ltd. All rights reserved. The development of phosphodiesterase type 5 (PDE5) inhibitors for the treatment of male erectile dysfunction (ED) has attracted great attention since the commercial introduction of Sildenafil (1, Viagra, Fig. 1). 1 PDE5, a cGMP hydrolytic enzyme, breaks down cGMP in the corpora cavernosa smooth muscle cells. Inhibition of PDE5 has been demonstrated to increase the levels of cGMP induced by nitric oxide (NO) from neuronal and endothelial sources during sexual stimulation. The increased cGMP levels, in turn, enhance the cavernosal smooth muscle relaxation, arterial inflow and venous congestion to achieve penile erection. 2 Despite its com- mercial success, Sildenafil has showed clinically sig- nificant side effects, some of which could be related to its low selectivity versus other PDEs such as PDE6. To discover potent and more selective PDE5 inhibitors for the treatment of male ED, we embarked on the design and synthesis of xanthine analogues based on com- pound 2 which was identified as a lead structure from high throughput screening. Herein, we would like to report the successful outcome of our efforts directed at discover- ing potent and selective xanthine PDE5 inhibitors. As shown in Figure 1, xanthine analogue 2 showed weak PDE5 inhibitory activity. To improve the PDE5 inhibitory activity and selectivity for this series of com- pounds, the structure–activity relationship (SAR) stud- ies of compound 2 were focused on chemical modification at the C8, N7, N1 and N3 positions. For the C8 modification, a variety of amino alcohols that have differences in their chirality, steric hindrance and aromatic character were tried. To further identify the SAR role of the hydroxy group of the amino alco- hols, two cycloamines were also included. These ana- logues were prepared as shown in Scheme 1. 3 Commercially available compound 3 was reacted with benzyl bromide to form compound 4. The bromide atom of compound 4 was displaced with different amines to give the final targets shown in Table 1. 0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(02)00646-7 Bioorganic & Medicinal Chemistry Letters 12 (2002) 3149–3152 Figure 1. Structures of PDE5 inhibitors. *Corresponding author. Tel.: +1-908-740-3508; fax: +1-908-740- 7152; e-mail: yuguang.wang@spcorp.com