Amide Derivatives of Meclofenamic Acid as Selective Cyclooxygenase-2 Inhibitors Amit S. Kalgutkar,* Scott W. Rowlinson, Brenda C. Crews and Lawrence J. Marnett A. B. Hancock, Jr., Memorial Laboratory for Cancer Research, Departments of Biochemistry and Chemistry, Center in Molecular Toxicology and the Vanderbilt Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Received 25 October 2001; accepted 20 November 2001 Abstract—This paper describes SAR studies involved in the transformation of the NSAID meclofenamic acid into potent and selective cyclooxygenase-2 (COX-2) inhibitors via neutralization of the carboxylate moiety in this nonselective COX inhibitor. # 2002 Elsevier Science Ltd. All rights reserved. Prostaglandins, particularly PGE 2 , are important med- iators of inflammation and pain and also provide cyto- protection in the stomach and intestine. The rate- limiting step in prostaglandin biosynthesis is the con- version of arachidonic acid to prostaglandin H 2 (PGH 2 ), in a reaction catalyzed by cyclooxygenase (COX). 1 COX activity originates from two distinct and independently regulated enzymes, termed COX-1 and COX-2. COX-1 is the constitutive isozyme and plays a role in cytoprotection and in maintaining normal renal function. COX-2 is inducible and short-lived; its expression is stimulated in response to a proin- flammatory insult. COX-2 plays a major role in pros- taglandin biosynthesis in inflammatory cells and in the central nervous system. 2 Nonsteroidal antiinflammatory agents (NSAIDs) inhibit the two isozymes to different extents, and this feature accounts for their shared therapeutic properties and side effects. 3 The differential tissue distribution of COX-1 and COX-2 has provided a rationale for the development of selective COX-2 inhibitors as nonulcerogenic, antiinflammatory and analgesic agents. 4,5 Two selective COX-2 inhibitors, celecoxib and rofecoxib are currently marketed as anti- inflammatory agents and two others (valdecoxib and etoricoxib) await FDA approval. We 6,7 and others 8 recently described a biochemically- based strategy for the facile conversion of carboxylate- containing NSAIDs. Thus, derivatization of the car- boxylate moiety in indomethacin to esters and amides produces selective COX-2 inhibitors. The facile nature of this strategy is evident from the observation that a single chemical derivatization step (amidation or ester- ification) generates an impressive array of potent and highly selective COX-2 inhibitors with oral antiinflam- matory activity. In this paper, we wish to disclose the details of the SAR studies on amide derivatives of the NSAID meclofenamic acid as COX-2-selective inhibitors. The desired ester and amide derivatives of meclofenamic acid (1) were prepared as shown in Scheme 1. Treatment of 1 with the appropriate alcohol or amine in the pre- sence of bis(2-oxo-3-oxazolidinyl)phosphonic chloride and triethylamine afforded the desired products in 60– 75% yield. IC 50 values for the inhibition of purified human COX-2 or ovine COX-1 by test compounds (Table 1) were 0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(01)00792-2 Bioorganic & Medicinal Chemistry Letters 12 (2002) 521–524 Scheme 1. Reagents and conditions: BOP-Cl, Et 3 N; (a) ROH; (b) RNH 2 . *Corresponding author. Tel.:+1-860-715-2433; fax:+1-860-715-4695; e-mail: amit_kalgutkar@groton.pfizer.com