Naphthol derivatives as TRPV1 inhibitors for the treatment of urinary incontinence Klaus Urbahns a,⇑ , Takeshi Yura a , Muneto Mogi a , Masaomi Tajimi a , Hiroshi Fujishima a , Tsutomu Masuda a , Nagahiro Yoshida a , Toshiya Moriwaki a , Timothy B. Lowinger a , Heinrich Meier b , Fiona Chan c , David Madge c , Jang B. Gupta a a Research Center Kyoto, Bayer Yakuhin, Ltd, Kizu, Soraku, Kyoto 619-0216, Japan b Bayer Healthcare, Aprather Weg, 42096 Wuppertal, Germany c Xention Limited, Iconix Park, London Road, Pampisford, Cambridge, CB22 3EG, United Kingdom article info Article history: Received 21 February 2011 Revised 29 March 2011 Accepted 3 April 2011 Available online 9 April 2011 abstract We have identified naphthol derivatives as inhibitors of the vanilloid receptor TRPV1 by high throughput screening. The initial lead showed high clearance in rats and has been optimized by enhancing the acidity of the phenol group. Compound 6b has reduced clearance, improved potency and is active in rat cystom- etry models of urinary incontinence after intravenous administration. Ó 2011 Elsevier Ltd. All rights reserved. TRPV1 (Transient receptor potential vanilloid 1, vanilloid recep- tor 1 or VR1) is an ion channel that gates after a variety of stimuli such as heat, acid or chemical agents like capsaicin (1a) or resinif- eratoxin (1b). It has been suggested that inhibiting TRPV1 could 0960-894X/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2011.04.013 ⇑ Corresponding author at present address: Merck KGaA, Frankfurter Strasse 250, 64293 Darmstadt, Germany. Tel.: +49 6151 72 6283; fax: +49 6151 72 3129. E-mail address: Klaus.Urbahns@merck.de (K. Urbahns). HN O HO MeO O H O O O O MeO O N S N H Cl HN N H O 1a: Capsaicin 2: Capsazepine 1b: Resiniferatoxin 3a: Lead from High Throughput Screening HO HO HO HO HO Figure 1. Structural comparison of HTS hit 3a with the agonists 1a/b and the known antagonist 2. Bioorganic & Medicinal Chemistry Letters 21 (2011) 3354–3357 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl