Discovery of diflunisal

Abstract

1 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 anti-inflammatory (3,2-c)-pyrazole steroids and phenyl-α-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-(1-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.