Letters in Drug Design & Discovery, 2005, 2, 329-340 329 Synthesis and Cyclooxygenase-2 (COX-2) Inhibiting Properties of 1,5- Diarylpyrazoles Possessing N-Substitution on the Sulfonamide (–SO 2 NH 2 ) Moiety † Manojit Pal a,* , Venugopal Rao Veeramaneni a , Sanjeev Kumar a , Akhila Vangoori b , Ramesh Mullangi b , Parimal Misra b , Shaikh Abdul Rajjak a , Vidya B. Lohray a , Seshagiri Rao Casturi b and Koteswar Rao Yeleswarapu a a Chemistry, b Biology, Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, India Received December 29, 2004: Accepted April 05, 2005 Abstract: A number of novel 1,5-diarylpyrazoles possessing N-substitution on the sulfonamide (–SO 2 NH 2 ) moiety were synthesized and tested for COX-1/COX-2 inhibition in vitro. Many of these 1,1-dioxo-2,3- dihydrobenzo[ d]isothiazolyl substituted 1,5-diarylpyrazoles, where the SO 2 NH 2 group was a part of the fused ring, showed COX inhibitory activity. Few of them were identified as selective COX-2 inhibitors. Structure Activity Relationship study within the series are discussed. Keywords: 1,5-Diarylpyrazoles, COX-1 & COX-2 inhibition, Structure Activity Relationship (SAR) study. INTRODUCTION osteoarthritis and rheumatoid arthritis is presently in phase III clinical development. Apart from its role in rheumatoid arthritis and osteoarthritis, COX-2 is also implicated in colon cancer and angiogenesis. [6a-c] Since the progression of Alzheimer’s disease has shown to be reduced among some users of NSAIDs, the chronic treatment with COX-2 inhibitors therefore may be effective for the treatment of inflammatory neurodegenerative disorders, without causing GI damage [6d]. 1,5-Diarylpyrazoles are the focus of many recent reports [1] because of their widespread use in the development of cyclooxygenase-2 (COX-2) inhibitors such as celecoxib. Selective COX-2 inhibitors currently provide effective treatment against pain and inflammation with reduced gastrointestinal side effects associated with traditional non- steroidal anti-inflammatory drugs (NSAIDs). NSAIDs reduce the pain and swelling of joints by inhibiting prostaglandin synthesis via blocking arachidonic acid (AA) oxygenation to prostaglandin G 2 (PGG 2 ). PGG 2 is the precursor to numerous prostaglandins including those that provide protection for the gastric mucosal. Until the discovery of second and inducible isozyme (COX-2) recently, a single cyclooxygenase (COX) enzyme was thought to be responsible for all of the catalysis of AA to PGG 2 . After the discovery of COX-2, the methanesulfonanilide (NS-398) and the diarylheterocycle (DUP-697) were first identified as non- ulcerogenic anti-inflammatory agents (Fig. 1) [2]. Subsequent research and rational drug design resulted in a number of potent and selective COX-2 inhibitors, which validated the initial concept that a selective COX-2 inhibitor would elicit effective anti-inflammatory activity without the adverse ulcerogenic effect associated with the use of NSAIDs that inhibit both COX-1 and COX-2. Accordingly, celecoxib [3] and rofecoxib [4], followed by valdecoxib [5a] and etoricoxib [5b] became the first and second-generation selective COX-2 inhibitors (Fig. 1) to enter the market. Very recently, parecoxib sodium [5c], a water-soluble prodrug of valdecoxib has also been marketed for the parenteral treatment of postoperative pain. In addition, a new COX-2 inhibitor lumiracoxib [5d] developed for the treatment of Several strategies have been reported on the modification of the known and non-selective inhibitors for the design and development of novel COX-2 inhibitors. These include lengthening or derivatization of the carboxylic side chain of the indomethacin [7a,b], development of 5-methylsulfonyl derivatives of indole-2-carboxylic acids (structurally related to indomethacin) [6c] and modification of the basic framework of zomepirac or flurbiprofen [7d,e]. The chemical structures of these COX-2 inhibitors including lumiracoxib, clearly indicate that the basic framework ofdiarylheterocycles is not the exclusive prerequisite for COX-2 inhibition. This was supported by the recent report on the development of novel tetrahydro-2 H-isoindoles as COX-2 inhibitor, where 1,2-disubstitution by two aryl groups on a central core was missing [7f]. In spite of several reports on deviation from the common structural features of diarylheterocycles i.e. 1,2- substitution and/ or the sulfonyl moiety on the aromatic ring, the main effort has been devoted to the diarylheterocycle class [7g-l] (as is exemplified by the recent report on the development of 1,5-diarylimidazoles [7i], 2,3- diarylindoles [7j], deracoxib [7k], 3,4-diarylpyran-2-ones [7l], DRF4848 [9f] etc. as COX-2 inhibitors), perhaps due to the early success in the discovery of two selective COX-2 inhibitors e.g. celecoxib and rofecoxib (while rofecoxib has been withdrawn from the market recently, its recall not necessarily indicates that all COX-2 inhibitors are equivalent and risky for human patients [4c] ). Celecoxib belongs to a diaryl heterocyclic class where two aryl moieties are attached *Address correspondence to this author at the Discovery Research, Dr. Reddy’s Laboratories Ltd., Bollaram Road, Miyapur, Hyderabad 500049, India; Fax: 91-40-23045438 /23045007; E-mail: manojitpal@drreddys.com † DRL Publication No. 340A. 1570-1808/05 $50.00+.00 © 2005 Bentham Science Publishers Ltd.