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

Authors: Kalgutkar A.S.; Zhao Z.

Source: Current Drug Targets, Volume 2, Number 1, March 2001 , pp. 79-106(28)

Publisher: Bentham Science Publishers

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

Language: English

Document Type: Review article

DOI: http://dx.doi.org/10.2174/1389450013348830

Publication date: 2001-03-01

• Current Drug Targets aims to cover the latest and most outstanding developments on the medicinal chemistry and pharmacology of molecular drug targets e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will be devoted to a single timely topic, with series of in-depth reviews, written by leaders in the field, covering a range of current topics on drug targets. These issues will be organized and led by a guest editor who is a recognized expert in the overall topic. As the discovery, identification, characterisation and validation of novel human drug targets for drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.

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