Aryl aminopyrazole benzamides as oral non-steroidal selective glucocorticoid receptor agonists Heather A. Barnett a , Diane M. Coe a , Tony W. J. Cooper a , Torquil I. Jack b , Haydn T. Jones a , Simon J. F. Macdonald a , Iain M. McLay c , Natalie Rayner a , Rosemary Z. Sasse d , Tracy J. Shipley b , Phil A. Skone b , Graham I. Somers a , Simon Taylor b , Iain J. Uings b , James M. Woolven c , Gordon G. Weingarten b, * a Respiratory CEDD, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK b Immuno-Inflammation CEDD, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK c Computational Analytical and Structural Sciences, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK d Screening & Compound Profiling, Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, UK article info Article history: Received 9 September 2008 Revised 28 October 2008 Accepted 29 October 2008 Available online 5 November 2008 Keywords: GR Glucocorticoid Aminopyrazole abstract Aryl aminopyrazole amides capped with N-alkylbenzamides 13–16 are selective glucocorticoid receptor agonists. 2,6-Disubstituted benzamides have prednisolone-like potency or better in vitro. Good oral exposure was demonstrated in the rat, with compounds with lower lipophilicity, for example N-hydroxy- ethyl benzamides (e.g., 16e). Ó 2008 Elsevier Ltd. All rights reserved. Glucocorticoid receptor (GR) agonists such as prednisolone 1 (Fig. 1) or fluticasone esters 2 have potent anti-inflammatory and immunosuppressive properties. There has been considerable effort in recent years to try to produce selective anti-inflammatory drugs which act as GR ligands that suppress the expression of inflamma- tory cytokines (transrepression activity) but do not affect genes associated with typical steroid side effects (transactivation activity) such as glucose intolerance, muscle wasting, skin thinning and oste- oporosis. 1–3 Boehringer–Ingelheim have demonstrated that a mole- cule with such dissociated pharmacology BI-115 3, had an improved side effect profile over 1 in a mouse model. 3 Another cause of off-tar- get pharmacology with some GR agonists is cross-reactivity with other members of the nuclear receptor (NR) family, such as the progesterone receptor (PR) androgen receptor (AR) and mineralo- corticoid receptor (MR). Selectivity in this respect has also been achieved with some non-steroidal compounds. 4,5 We have previously reported a series of GR agonists containing a tetrahydronaphthalene (THN) group, for example, 5a,b, in which both NR and transrepression (TR) selectivity can be achieved. 4,5 The angular alkyl group R in 5a,b is crucial for agonist activity and it was designated an agonist trigger. Compound 5a, in which R is ethyl, is a full agonist in both TR and transactivation (TA) assays, whereas 5b, in which R is cyclopentyl, is selective for TR. In this series, we found that the aryl aminopyrazole group is a good replacement for the steroidal cyclohexadienone A-ring. We 5 and other groups 6–8 report the use of an aryl indazole, reminiscent of that present in cortivazol 4a. The X-ray crystal structure of deac- ylcortivazol 4b bound into the GR ligand binding domain (LBD) 9 showed that the space occupied by the steroidal A-ring in the ac- tive site, can open up to accommodate the arylpyrazole structure. Although the THN series had attractive pharmacology, it was structurally complex and more hydrophobic than typical oral drugs. We thus envisaged replacing the THN portion by an aryl group linked to the remainder of the molecule by a hydrophilic lin- ker such as an amide, to give molecules 13–16 (Scheme 1) with physicochemical properties more appropriate for oral drugs. The aryl group was designed to occupy the hydrophobic pocket popu- lated by the 17a ester group in FP and FF 2, and R 1 the position occupied by the trigger group R in the THN series. Molecular modelling of a typical example, the 2,6-dichloro- benzamide 13h, supported this concept. The structural information about the GR LBD from our recently published fluticasone furoate structure 10 was used to provide the starting point for the docking experiments used to help guide this work. The docking models were created using FLO+ which allows flexibility of side chains during docking. 5 The model created for this series is compared in Figure 2a–c with the previous model developed for arylpyrazoles 5 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.10.128 * Corresponding author. E-mail address: ggw1517@yahoo.com (G.G. Weingarten). Bioorganic & Medicinal Chemistry Letters 19 (2009) 158–162 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl