Development of Highly Selective COX-2 Inhibitor

Journal/Book: Z Rheumatol 1998; 57 Suppl. 1: 13 (V 44). 1998;

Abstract: Merck Frosst Centre for Therapeutic Research Kirkland Cyclooxygenase (prostaglandin synthase) catalyzes the oxygenation of arachidonic acid to prostaglandin H2 as a first step in the synthesis of prostaglandins prostacyclins and thromboxanes. The enzyme is expressed in mammalian cells as two distinct isosymes that show about 60 % amino acid sequence identity. Cox-1 is the major form expressed in healthy tissues and plays a role in thrombogenesis and in the homeostasis of the gastrointestinal tract and kidneys. Cox-2 synthesis is inducible in many cell types by bacterial endotoxin cytokines including IL-1 and TNF( mitogens and growth factors and is repressed by dexamethasone. Both enzymes are sensitive to inhibition by conventional nonsteroidal anti-inflammatory drugs (NSAIDs). The observations that Cox-2 is associated with inflammatory conditions and that Cox-1 is mainly expressed as a constitutive enzyme have provided the rationale for the development of selective Cox-2 inhibitors in order to reduce the risk of gastric irritation and ulceration associated with the chronic use of NSAIDs. Preclinical and early clinical data supports the hypothesis that selective Cox-2 inhibitors will have anti-inflammatory analgesic and anti-pyretic activities comparable to NSAIDs with a substantial reduction in some of the side effects associated with this class of drugs particularly induction of gastric lesions and effects on bleeding times. Mechanistic studies indicate that a high degree of selectivity for Cox-2 will be required for effective functional selectivity in vivo. A second generation of highly selective Cox-2 inhibitors has been discovered. This class of inhibitors is more selective for Cox-2 than MK-966. For example an optimized compound has an IC50 of 60 nM in a CHO Cox-2 assay and IC50 of 0.3 µM in the Cox-2 LPS-induced human whole blood assay. ... le

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