3-Indolyl sultams as selective CRTh2 antagonists L. Nathan Tumey * , Michael J. Robarge, Elizabeth Gleason, Jianping Song, Steven M. Murphy, George Ekema, Chris Doucette, Doug Hanniford, Marc Palmer, Gary Pawlowski, Joel Danzig, Margaret Loftus, Karen Hunady, Bruce Sherf, Robert W. Mays, Alain Stricker-Krongrad, Kurt R. Brunden, Youssef L. Bennani, John J. Harrington Athersys, Inc., 3201 Carnegie Ave., Cleveland, OH 44115, USA article info Article history: Received 8 February 2010 Revised 8 April 2010 Accepted 12 April 2010 Available online 14 April 2010 Keywords: CRTh2 DP Ramatroban Antagonist Prostaglandin D2 Sultam Indole abstract CRTh2 (DP 2 ) is a prostaglandin D 2 receptor implicated in the recruitment of eosinophils and basophils within the asthmatic lung. Here we report the discovery of a novel series of 3-indolyl sultam antagonists with low nM affinity for CRTh2. These compounds proved to be selective over the other primary prosta- glandin D 2 receptor (DP1) as well as the thromboxane A 2 receptor (TP). Ó 2010 Elsevier Ltd. All rights reserved. Prostaglandin D 2 (PGD 2 ) produced by mast cells is a key media- tor of asthmatic and allergic inflammatory responses. 1 There are two known receptors of PGD 2 : DP1 and DP2 (also known as CRTh2). 2–4 The latter receptor is expressed on the surface of eosin- ophils, basophils, and Th2 cells and is responsible for PGD 2 -induced chemotaxis in all three cell types. 5 Moreover, CRTh2 is involved in cytokine release from Th2 cells and degranulation of eosinophils. 6,7 This has led to widespread interest in antagonists of CRTh2 as po- tential agents for the treatment of asthma and related allergic dis- eases. 8–13 Recent publication of the effect of CRTh2 antagonists in various animal models of asthma and allergic rhinitis have spurred further interest in the exploration of this target. 14–16 Ramatroban and its acetic acid analog (1, Fig. 1) have been re- ported to be potent antagonists of CRTh2. 17,18 We previously dis- closed the SAR of a series of ‘reverse Ramatroban’ analogs with similar potency to compound 1. 10 In our attempts to design addi- tional novel CRTh2 antagonists, we hypothesized that the satu- rated ring of compound 1 could be excised from the tetrahydrocarbazole and instead form a bicyclic sulfonamide, as shown in Figure 1. One such embodiment of this hypothesis is ben- zosultam 3. This analog seemed especially fitting given that it would retain and rigidify the cisoid geometry that sulfonamides such as Ramatroban naturally adopt. The synthesis of compound 3 and related compounds is illustrated in Scheme 1. The synthesis begins with AlCl 3 promoted electrophilic addition of compound 2 (derived in one step from saccharin) 19 to an indole, giving interme- diate A. The indole nitrogen of A is alkylated with t-butyl bromo- acetate and the sulfonyl imine is subsequently reduced to give the benzosultam C. Deprotection of the tert-butyl group is accom- plished with TFA giving compounds 3–10. Compound 3 proved to be only weakly active as an antagonist of CRTh2, with binding affinity (K i ) of approximately 9.2 lM(Table 1). Incorporation of various substituents at the 5-position (4–6) im- proved affinity by 2–3-fold. Incorporation of methyl at the 2-posi- tion (7) also increased binding by threefold. The effect of substituents at the 2- and 5-positions proved to be additive, as 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.04.046 * Corresponding author. Tel.: +1 845 602 1876; fax: +1 845 602 5561. E-mail addresses: tumeyn@wyeth.com, nathantumey@yahoo.com (L.N. Tumey). N HO 2 C ( ) n NH S O O F n = 2: Ramatroban n = 1: 1 N R X Y HO 2 C NH S O O N HO 2 C NH S O O 3 1 2 3 4 5 6 7 Figure 1. Stuctures of Ramatroban and lead molecule 3. Bioorganic & Medicinal Chemistry Letters 20 (2010) 3287–3290 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl