Discovery and Design of Selective Cyclooxygenase-2 Inhibitors as Non-Ulcerogenic, Anti-Inflammatory Drugs with Potential Utility as Anti-Cancer Agents

Amit   S.   Kalgutkar; Zhiyang      Zhao

Abstract

The recent marketing of two selective cyclooxygenase-2 (COX-2) inhibitors, celecoxib and rofecoxib is remarkable considering that COX-2 was only discovered eight years ago as a growth factor- and cytokine-inducible gene. Concomitant with these pharmaceutical successes is the advances in our understanding of the molecular and structural basis for selective COX-2 inhibition. This review provides a perspective on the ongoing structure-activity relationship (SAR) efforts in the search of COX-2-specific inhibitors with particular reference to their structural basis for isozyme-specific inhibition. In addition to the existing inhibitor classes, this review will also highlight many novel structural classes which have recently emerged due to a better understanding of the active site differences between the two isozymes with a special emphasis on the modification of the well-established non-steroidal anti-inflammatory drug (NSAID) scaffold. In addition to its role in inflammation, recent studies suggest that COX-2-derived prostaglandins may play a pivotal part in the maintenance of tumor viability, growth, and metastasis. In this review, we summarize the NSAID epidemiological evidence, studies demonstrating overexpression of COX-2 in multiple human tumors and pharmacological evidence in animal models, which indicate that COX-2 inhibitors could be used in the prevention or treatment of a broader range of disease.

Keywords: Cyclooxygenase-2 Inhibitors, Non-Ulcerogenic, Anti-Inflammatory, Anti-Cancer Agents, Growth factor, Cytokine-inducible gene, COX-2 specific inhibitors, Human Tumors, Acidic sulfonamides