Discovery of diflunisal.

Abstract

I Diflunisal (MK-647; 5-(2,4-difluorophenyl)-salicylic acid) is a new analgesic anti-inflammatory agent discovered after an extensive chemical and pharmacological study from 1962-71. 2 In the search for a superior salicylate our objectives were higher potency, better tolerance, and a longer duration of action. 3 An evaluation of many available and newly synthesized salicylates, in the granuloma and carrageenan foot oedema assays, revealed the activity-enhancing trend of a hydrophobic group-for example, phenyl, at the carbon-5 position of salicylic acid. 4 The attachment of a 5-(4-fluorophenyl) group, previously found to enhance the potency of antiinflammatory (3,2-c)-pyrazole steroids and phenyl-a-propionic acids to acetyl salicylic acid yielded a clinical candidate flufenisal. As an analgesic, flufenisal is two times more potent than aspirin in man, but with a longer action; no distinct advantage in gastrointestinal tolerance has, however, been observed. 5 Further investigation of 5-heteroaryl salicylic acids, flufenisal congeners and their non-acylating carbonate esters identified diflunisal and 5-( l-pyrryl)-salicylic acid for subacute safety assessment. The O-acetyl group, commonly present in aspirin, benorylate and flufenisal, was purposely avoided in these two compounds for safety considerations. 6 Without an O-acetyl group, diflunisal cannot acetylate proteins and macro-molecules in vivo as aspirin does. In the prostaglandin synthetase assay in vitro, salicylic acid is much less active than aspirin. In contrast, the non-acetylated diflunisal and desacetyl flufenisal are both more active than flufenisal in vitro. A significant difference between aspirin and diflunisal in their biochemical mechanisms was noted. 7 On the basis of overall efficacy and tolerance data, diflunisal was finally chosen as a superior analgesic anti-inflammatory salicylate for clinical evaluation.

Prostaglandin Synthetase Inhibitors

“…However, the O-acetyl group, and the consequent ability to acetylate cyclooxygenase, are not necessary for antiinflammatory-analgesic actions of substituted salicylates. For example, the 5-difluorophenyl derivative of salicylic acid, diflunisal, is a more potent and longer acting analgesic antiinflammatory agent (19). It inhibits the PG synthetase system prepared from sheep seminal vesicle at 2 ~M (20).…”

Review of the Animal and Clinical Pharmacology of Diflunisal

“…1 In 1971, after synthesis of more than 500 compounds and limited clinical testing of an earlier analog (flufenisal) which failed in part because it offered no improvement in therapeutic index over aspirin, diflunisal was identified. 2 A number of reviews3-9 and proceedings of meetingsHH 2 on this drug have been published. This review will expand and update this information.…”

Chemical and Pharmacological Properties of Diflunisal

“…The discovery of diflunisal culminated a long, chemical and pharmacologic effort in the Merck Sharp & Dohme Research Laboratories toward such a goal. 2 As illustrated in Formulas 1 and 2 (Figure 1 ), diflunisal differs from aspirin in two structural features.…”