Dioxo-triazines as a novel series of cathepsin K inhibitors Zoran Rankovic a, * , Jiaqiang Cai a, * , Xavier Fradera a , Maureen Dempster a , Ashvin Mistry a , Ann Mitchell a , Clive Long a , Emma Hamilton a , Angela King a , Sylviane Boucharens a , Craig Jamieson a , Jonathan Gillespie a , Iain Cumming a , Joost Uitdehaag b , Mario van Zeeland b a Schering-Plough Corporation, Newhouse, Lanarkshire, ML1 5SH, Scotland, United Kingdom b Schering-Plough Corporation, 5340BH Oss, The Netherlands article info Article history: Received 3 December 2009 Revised 20 January 2010 Accepted 21 January 2010 Available online 25 January 2010 Keywords: Cathepsin K Cysteine protease Osteoporosis abstract A novel dioxo-triazine series of cathepsin K inhibitors was identified from HTS. A rapid exploratory pro- gramme led to the discovery of potent and selective cathepsin K inhibitors, typified by compound 24 which displayed IC 50 values of 17 nM against catK and >10,000 nM in catL, catB and catS assays. Ó 2010 Elsevier Ltd. All rights reserved. Osteoporosis is a systemic, degenerative skeletal condition char- acterised by low bone mass and micro architectural deterioration of bone, leading to reduced bone strength. 1 It most commonly affects postmenopausal women, but also occurs in premenopausal women, and in men, often being induced by a variety of secondary causes. The resultant low bone mineral density (BMD) makes osteoporotic pa- tients prone to fractures, which can lead to serious complications and fatality. The abundant and selective expression of cathepsin K in osteoclasts, cells involved in bone resorption, indicates its poten- tially critical role in bone remodelling. 2 Indeed, a number of cathep- sin K mutations have been found to be associated with pycnodysostosis, a recessive bone sclerosing disorder characterised by increased bone density (osteopetrosis), dwarfism and skeletal abnormalities. Cathepsin K knockout mice display similar skeletal abnormalities, including osteopetrosis, further corroborating the key role of cathepsin K in bone remodelling. 3 Cathepsin K is a lyso- somal cysteine protease from the papain family which contains a highly conserved catalytic triad Cys25, His159 and Asn175 within its active site (papain numbering). Eleven members of this family are known to be expressed in the human genome, of which cathepsins L, S and V are most closely re- lated to cathepsin K. 4 Development of selective cathepsin K inhib- itors for treatment of osteoporosis attracted considerable attention in recent years. 5 Such compounds displayed ex vivo efficacy in osteoclast-based assays of bone resorption and in vivo efficacy in rodent 6 and primate models of postmenopausal osteoporosis 7 and most recently in patients within clinical settings. 8 High throughput screening of the corporate compound file against cathepsin K led to the identification of 6-cyano-2-(3 0 -trifluo- romethyl-phenyl)-3,5-dioxo-1,2,4-triazine 1. Despite 1 being a sin- gleton hit with poor catK potency (IC 50 = 2000 nM) and low aqueous solubility (<1 mg/L), this was an interesting discovery since at the time only peptidic catK inhibitors were known in the litera- ture. 9 Hence, an exploratory programme was instigated to evaluate progressability of this chemotype. The synthesis of the dioxo-triazine 1 is described in Scheme 1. 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.01.116 * Corresponding authors. Tel./fax: +44 1698736157 (Z.R.). E-mail addresses: zoran.rankovic@spcorp.com (Z. Rankovic), jiaqiang.cai@sp corp.com (J. Cai). N H NH N O O Br N NH N O O Br N NH N O O CN N N N O O CN CF 3 1 i ii iii 2a 2b 2c 6 4 2 Scheme 1. Reagents and conditions: (i) KHCO 3 , n-PrI, DMSO, rt, 1 h; (ii) tetramethyl urea, CuCN, 145 °C, 3 h; (iii) Cu(OAc) 2 , 3-CF 3 PhB(OH) 2 , CH 2 Cl 2 , rt, 18 h. Bioorganic & Medicinal Chemistry Letters 20 (2010) 1488–1490 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl