Diaminocyclobutenediones as potent and orally bioavailable CXCR2 receptor antagonists: SAR in the phenolic amide region Cynthia Aki a , Jianping Chao a , Johan A. Ferreira a , Michael P. Dwyer a , Younong Yu a , Jianhua Chao a , Robert J. Merritt d , Gaifa Lai d , Minglang Wu d , R. William Hipkin c , Xuedong Fan c , Waldemar Gonsiorek c , James Fosseta c , Diane Rindgen b , Jay Fine c , Daniel Lundell c , Arthur G. Taveras a , Purakkattle Biju a, * a Department of Chemical Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA b Department of Drug Metabolism, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA c Department of Biological Research, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA d Pharmacopeia Drug Discovery Inc., 3000 Eastpark Boulevard, Cranbury, NJ 08512, USA article info Article history: Received 4 April 2009 Revised 12 May 2009 Accepted 13 May 2009 Available online 18 May 2009 Keywords: Diaminocyclobutenediones CXCR2 receptor antagonist Amide modification abstract A series of potent and orally bioavailable 3,4-diaminocyclobutenediones with various amide modifica- tions and substitution on the left side phenyl ring were prepared and found to show significant inhibitory activities towards both CXCR2 and CXCR1 receptors. Ó 2009 Elsevier Ltd. All rights reserved. The recruitment of leukocytes into sites of inflammation is a normal biological process to fight infection. However, in diseases such as rheumatoid arthritis, COPD and psoriasis, the uncontrolled leukocyte migration to the site of inflammation may be the leading cause of permanent tissue destruction and further disease progres- sion. As a result of inflammatory stimuli, chemokines 1 released by a wide variety of cells signal the migration of macrophages, T-cells, eosinophils, basophils, neutrophils and endothelial cells to sites of inflammation and tumor growth. In general, chemokines have been classified 2 into two main classes, the CXC-chemokines and the CC-chemokines. The CXC-chemokines 3 include interleukin-8 (IL-8), neutrophil activating protein-1 (NAP-1), NAP-2 and GRO-a as well as many others. These CXC-chemokines promote the accu- mulation and activation of neutrophils and hence, they have been implicated in a wide range of acute and chronic inflammatory dis- orders 4 including psoriasis, rheumatoid arthritis and COPD. IL-8 mainly activates neutrophils through their G-protein coupled receptors, CXCR1 and CXCR2. The increased levels 5 of IL-8, GRO- a and MCP-1 in the sputum from patients with COPD compared to non smokers highlight the importance of chemokine targets for small molecule drug discovery. Due to the well established relationship between IL-8 and inflammatory diseases, CXCR1 and CXCR2 antagonists 6 have been targets of small molecule drug discovery. Several literature reports are available on the discovery of CXCR2 antagonists. 7,8 We previ- ously reported several publications on the structure–activity rela- tionships of 3,4-diaminocyclobutenedione 8a–e (e.g., 1) class of CXCR2 antagonist, 3,4-diaminothiadiazoleoxides 8f 2 and 3 and 3,4-diamino-1,2,5-thiadiazoles 8g 4. Our earlier reports primarily focused on the structure–activity relationships of the right side amine modifications. Herein, we report the R 1 and R 2 modifications on the left side phenolic amide region (Fig. 1). Structure–activity relationships of the compounds listed in Table 1 shows the basic structural elements required to show CXCR2 receptor antagonism in the 3,4-diaminocyclobutenedione class of compounds. The weaker binding affinity of the ben- zomorpholine compound 9, the N-methyl compounds 11 and 12 and the methoxy compound 13 established the basic requirement of three critical H-bonding functional groups, the phenolic OH group and the two –NH-groups (Table 1). The carboxylic acid compound 7, the unsubstituted amide 8 and the 2-amino phenol compound 10 showed reasonable binding affinity towards the CXCR2 receptor. On the other hand, the N,N-di- methyl amide 6 and 17 (Table 2) displayed excellent inhibitory activities. This initial SAR prompted us to explore additional amide modifications, which is depicted in Table 2. The synthetic procedures for the preparation and coupling of various left and right side amines to the commercially available 3,4- diethoxysquarate can be obtained from our previous publications. 8,9 0960-894X/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2009.05.049 * Corresponding author. Tel.: +1 908 740 3127; fax: +1 908 740 7152. E-mail address: purakkattle.biju@spcorp.com (P. Biju). Bioorganic & Medicinal Chemistry Letters 19 (2009) 4446–4449 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl