Structure–activity relationships and pharmacokinetic parameters of quinoline acylsulfonamides as potent and selective antagonists of the EP 4 receptor Jason D. Burch, * Michel Belley, Re ´jean Fortin, Denis Desche ˆnes, Mario Girard, John Colucci, Julie Farand, Alex G. Therien, Marie-Claude Mathieu, Danielle Denis, Erika Vigneault, Jean-Franc ¸ois Le ´vesque, Se ´bastien Gagne ´, Mark Wrona, Daigen Xu, Patsy Clark, Steve Rowland and Yongxin Han * Merck Frosst Centre for Therapeutic Research, 16711 Trans-Canada Highway, Kirkland, Que., Canada H9H 3L1 Received 19 December 2007; revised 24 January 2008; accepted 25 January 2008 Available online 31 January 2008 Abstract—A new series of EP 4 antagonists based on a quinoline acylsulfonamide scaﬀold have been identiﬁed as part of our on- going eﬀorts to develop treatments for chronic inﬂammation. These compounds show subnanomolar intrinsic binding potency towards the EP 4 receptor, and excellent selectivity towards other prostanoid receptors. Acceptable pharmacokinetic proﬁles have also been demonstrated across a series of preclinical species. Ó 2008 Elsevier Ltd. All rights reserved. Prostanoids (prostaglandins and thromboxanes) are important lipid hormones formed from arachidonic acid metabolism. Prostaglandin E 2 (PGE 2 ), in particular, is the principal proinﬂammatory prostanoid and is impli- cated in the pathogenesis of a number of diseases such as pain, fever, arthritis and cancer. Inhibition of PGE 2 production by NSAIDs and COX-2 inhibitors (Coxibs) relieves arthritis symptoms, and thus is the basis of widespread uses of these drugs as analgesics. 1 Unfortu- nately, the therapeutic utilities of these drugs are limited by their potential to cause either gastro-intestinal toxic- ity (by NSAIDs) 2 or cardiovascular (CV) side eﬀects (by both NSAIDs and Coxibs). 3 The CV adverse events associated with these drugs are not clearly understood although it is speculated that inhibition of prostacyclin biosynthesis may cause the prothrombotic and hyper- tensive eﬀects. 4 Therefore, there is a vast unmet medical need to discover alternatives for treating chronic ail- ments such as arthritis. PGE 2 exerts its biological eﬀects through four subtype EP receptors, EP 1–4 . In a mouse model of collagen-anti- body induced arthritis (CAIA), the EP 4 = mice showed a remarkable resistance to both the incidences and symptom scores (paw swelling/redness, ankylosis) of arthritis compared to the wild type controls while the EP 1–3 = mice showed no eﬀect, suggesting that the eﬀect of PGE 2 in chronic inﬂammation was mediated predom- inantly by the EP 4 receptor. 5 Lin et al. demonstrated that EP 4 , not EP 1–3 , contributed to inﬂammatory pain hypersensitivity in rats, providing further evidence that EP 4 antagonism is a valid strategy for treating inﬂam- matory pain. 6 It is plausible that a selective EP 4 antago- nist may ameliorate symptoms of chronic inﬂammation without the potential CV side eﬀects observed with NSAIDs and COX-2 inhibitors since it does not inter- fere with biosynthesis of any prostanoids including pros- tacyclin and thromboxanes. In addition to its role in inﬂammation, the EP 4 receptor has also been implicated in destabilizing atherosclerotic plaques in human 7 and in developing tumour metastasis. 8 Therefore, EP 4 antago- nists represent potential promising new therapeutic agents for treating inﬂammatory pain, atherosclerosis and cancer. In this paper, we describe the discovery of a highly potent EP 4 antagonist with excellent pharmaco- kinetic properties and in vivo potency. At the outset of our investigations, acylsulfonamide 1 was a known EP 4 antagonist from the literature 0960-894X/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2008.01.103 Keywords: Anti-inﬂammatories; Prostanoid receptor antagonists; Quinoline acylsulfonamides. * Corresponding authors. Tel.: +1 514 428 3839; e-mail: jason_burch@merck.com Available online at www.sciencedirect.com Bioorganic & Medicinal Chemistry Letters 18 (2008) 2048–2054