Dipeptidyl nitrile inhibitors of Cathepsin L Nabil Asaad a , Paul A. Bethel a , Michelle D. Coulson b , Jack E. Dawson a , Susannah J. Ford a , Stefan Gerhardt a , Matthew Grist a , Gordon A. Hamlin a , Michael J. James a , Emma V. Jones a , Galith I. Karoutchi a , Peter W. Kenny a, * , Andrew D. Morley a, * , Keith Oldham a , Neil Rankine a , David Ryan a , Stuart L. Wells a , Linda Wood a , Martin Augustin c , Stephan Krapp c , Hannes Simader c , Stefan Steinbacher c a Respiratory & Inflammation Research Area, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK b Safety Assessment, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, UK c Proteros Biostructures, Am Klopferspitz 19, D-82152 Martinsried, Germany article info Article history: Received 20 April 2009 Revised 20 May 2009 Accepted 21 May 2009 Available online 27 May 2009 Keywords: Cathepsin Cathepsin B Cathepsin K Cathepsin L Cathepsin L2 Cathepsin S Cathepsin V Cysteine protease Nitrile Covalent inhibitor Selectivity Protein structure X-ray crystallography Structure-based design Molecular pincer Conformational lock Tautomeric lock Osteoarthritis Aggrecan Collagen Cartilage abstract A series of potent Cathepsin L inhibitors with good selectivity with respect to other cysteine Cathepsins is described and SAR is discussed with reference to the crystal structure of a protein-ligand complex. Ó 2009 Elsevier Ltd. All rights reserved. Osteoarthritis is a chronic degenerative disease, resulting from loss of articular cartilage and damage to underlying bone, leading to joint instability and pain. 1 The lysosomal cysteine protease 2 Cathepsin L (CatL) is seen as a potential target for intervention in treatment of this disease. 3 The enzyme is secreted into the extra- cellular matrix and has been shown in vitro that it can degrade proteoglycans, including aggrecan 4 and type II collagen, 5 the major components of articular cartilage. Selectivity with respect to other Cathepsins is an important consideration. Cathepsins B (CatB) and L2 (CatL2) are key anti-tar- gets in optimization of CatL inhibitors. In mice the combined defi- ciency of CatB and CatL has been shown to be lethal in the second to fourth week of life. 6 CatL À/À mice show abnormalities in skin and hair differentiation. 7 The human genome encodes a CatL-like cysteine protease (CatL2), which shows a restricted tissue distribu- tion and is not present in the mouse genome. Studies using CatL À/À mice showed that transgenic, keratinocyte-specific expression of human CatL2 largely rescued the skin and hair phenotype, indicat- ing that this protease may play an important role in human skin homeostasis. 8 Both CatL and CatS have roles in MHC class II-med- iated antigen processing and presentation and may compensate for 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.05.071 * Corresponding authors. Tel.: +44 1625 514396 (P.W.K.), +44 1509 644772 (A.D.M.). E-mail addresses: pwk.pub.2008@gmail.com (P.W. Kenny), andy.morley@astra zeneca.com (A.D. Morley). Bioorganic & Medicinal Chemistry Letters 19 (2009) 4280–4283 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl