The structure of human aldose reductase bound to the inhibitor IDD384.

The crystallographic structure of the complex between human aldose reductase (AR2) and one of its inhibitors, IDD384, has been solved at 1.7 A resolution from crystals obtained at pH 5.0. This structure shows that the binding of the inhibitor's hydrophilic head to the catalytic residues Tyr48 and His110 differs from that found previously with porcine AR2. The difference is attributed to a change in the protonation state of the inhibitor (pK(a) = 4.52) when soaked with crystals of human (at pH 5.0) or pig lens AR2 (at pH 6.2). This work demonstrates how strongly the detailed binding of the inhibitor's polar head depends on its protonation state.

Tissue selective inhibition of prostaglandin biosynthesis by etodolac.

Inflammation is a complex process involving numerous mediators. Because prostaglandins (PG) have been implicated as mediators in all stages of inflammation, inhibition of their synthesis provides the basis for the therapeutic effects of nonsteroidal antiinflammatory drugs (NSAID). Treatment with NSAID is usually accompanied by gastric side effects, attributed to interference with the formation of cytoprotective PG in gastric mucosa. An ideal NSAID should inhibit PG synthesis at the site(s) of inflammation but not in gastric mucosa. Experimental and clinical data support the view that this criterion has been met by etodolac, a structurally distinct NSAID. Thus, in rats and humans with rheumatoid arthritis, longterm daily administration of etodolac at effective antiinflammatory dosages (3 mg/kg in rats; 600 mg in humans) had no effect on PGF2 and prostacyclin levels in gastric mucosa. In contrast, significant decreases in gastric PG levels occurred with antiinflammatory doses of aspirin, naproxen, and piroxicam. Cyclooxygenase (COX), the pivotal enzyme in PG biosynthesis, exists in 2 isoforms: constitutive COX-1, which produces the PG required for maintenance of normal cell activity (e.g., gastric cytoprotection), and COX-2, which is induced in restricted tissue-specific fashion (e.g., by inflammatory stimuli). The antiinflammatory action of NSAID may result from inhibition of COX-2, whereas their gastric side effects may result in large part from inhibition of COX-1; thus, a preferred NSAID should inhibit COX-2 but not COX-1. Results show that etodolac has 10-fold selectivity for COX-2 and indicate that etodolac's pharmacotherapeutic efficacy can be explained by its demonstrably selective inhibition of COX-2, amplified by its favorable tissular pharmacokinetics. The sparing of COX-1 activity in gastric mucosa gives rise to etodolac's noted gastric tolerance.