Solid-State Properties of the Cyclooxygenase-1-Selective Inhibitor, SC-560

 Sihui Long, Kathryn L. Theiss, Alessandra Mattei, Charles D. Loftin, and Tonglei Li
AAPS PharmSciTech, 11:485-488, 2010

Abstract (from publisher): Selective inhibition of the cyclooxygenase-1 (COX-1) isoform has been shown to reduce inflammation and tumorigenesis and lack the gastrointestinal toxicity of traditional nonsteroidal anti-inflammatory drugs. The COX-1-selective inhibitor 5-(4-chlorophenyl)-1-(4-methoxyphenyl)-3-(trifluoromethyl)-1H-pyrazole (SC-560), shown in Fig. 1, was identified as one of several structurally related compounds with varying selectivity for the COX isoforms during the development of the COX-2-selective inhibitor celecoxib (1). From this work, SC-560 was found to be a highly selective and potent inhibitor of COX-1, with in vitro studies showing an IC50 of 0.007 μM for COX-1 and 75 μM for COX-2. In animal studies, SC-560 has been shown to be effective in treating neuroinflammation when administered by injection (2). However, the poor bioavailability that results following oral administration of SC-560 may limit its effectives in treating diseases where COX-1 inhibition would provide efficacy. When administered orally to rats as a suspension in 1% methylcellulose, the mean bioavailability is only 5% of the dose (3). Altering the oral dosage formulation by dissolving in polyethylene glycol 600 improves the bioavailability to only 15% (3). Therefore, additional studies are needed to identify dosage formulations which may improve oral bioavailability. To develop dosage forms and products of a potential drug compound, solid-state properties of the chemical need to be thoroughly examined. One of the basic attributes is the crystal structure of the compound, which determines important physical and chemical properties of the substance, including solubility and dissolution rate. We have solved the crystal structure for SC-560 and reported it elsewhere (4). Herein, we describe additional solid-state properties, including its solubility in water.

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