Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1991-02-19
1993-02-16
Springer, David B.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
548492, 548500, C07D20926, A61K 31405
Patent
active
051871874
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
This invention relates to novel compounds which function as irreversible ligands for nonsteroidal antiinflammatory drug (NSAID) and prostaglandin binding sites.
Nonsteroidal antiinflammatory drugs are drugs of choice in the treatment of arthritis and other inflammatory disorders. It is widely accepted that NSAIDs inhibit the enzyme Prostaglandin H.sub.2 synthase (PGH synthase) and prevent the synthesis of the primary prostaglandins which mediate some symptoms of inflammation. Since its introduction into the pharmaceutical market in 1963, indomethacin (I) has become the standard to which all other NSAIDs are compared. ##STR1## Another class of compounds which are equipotent with the indole acetic acids in their ability to inhibit PGH synthase are the N-phenylanthranilic acids, represented by meclofenamic acid (II) and diclofenac (III). The pyrrole acetic acids, represented by tolmetin (IV) and zomepirac (V), are slightly less potent inhibitors of PGH synthase. ##STR2##
Although the putative target enzyme, PGH synthase, has been purified to homogeneity and its sequence deduced from its cDNA, no good topographical map of the antiinflammatory drug binding site of PGH synthase currently exists. Until antiinflammatory drug-receptor interactions are explicitly understood at the molecular level, progress in the rational design of superior drugs is hindered.
This issue is complicated by the fact that PGH synthase may not be the only target for NSAID action. Since this enzyme is not inhibited by sodium salicylate, a presumptive active ingredient of acetyl salicylate (aspirin), alternative targets for the action of NSAIDs have been proposed Prostaglandin dehydrogenases are a family of AND(P)+-linked oxidoreductases that display some regioand stereoselectivity for the oxidation of hydroxyprostaglandins. Several of these enzymes are inhibited in a reversible fashion by NSAIDs Inhibition of prostaglandin transformation at this level may contribute to the mechanism of action of NSAIDs.
Another possible target enzyme is 3.alpha.-hydroxysteroid dehydrogenase of rat liner cytosol (3.alpha.-HSD, E.C. 1.1.1.50). The homogeneous 3.alpha.-HSD of rat liver cytosol is an unusual oxidoreductase in that it will catalyze the interconversion of 3.alpha.- (axial) alcohols to ketones on the steroid nucleus, and will function as a 9, 11 and 15- hydroxyprostaglandin dehydrogenase. 3.alpha.-HSD is potently inhibited at its active site by all the major classes of NSAIDs. By virtue of its prostaglandin dehydrogenase activity, it may represent an alternative site for NSAID action. It fulfills many of the criteria expected of a target enzyme: the concentrations of drugs required to inhibit 3.alpha.-HSD are comparable to those required to inhibit PGH synthase; the rank order of inhibitory potency of NSAIDs for 3.alpha.-HSD correlates extremely well with the human dose required to produce their pharmacological effect; the enzyme can distinguish between active and inactive geometric isomers of NSAIDs. On this basis, a rapid spectrophotometric screen has been developed for the enzyme, which can be used to screen potential antiinflammatory drugs. In addition, 3.alpha.-HSD catalyzes a pro-inflammatory reaction (PGF.sub.2.alpha. to PGE.sub.2) which is blocked by NSAIDs. The indomethacin sensitive 3.alpha.-HSD is widely distributed in rat tissues, with the enzyme of highest specific activity being found in liver, then lung, testis, heart, prostate, spleen, seminal vesicle, and brain. Despite 3.alpha.-HSD's involvement in steroid hormone metabolism, the enzyme is not present in highest levels in those tissues traditionally associated with endocrine function, but is high in those that rapidly metabolize prostanoids (lung and heart). (For a Review see Steroids, 47, 221-247 (1986)).
Since 3.alpha.-HSD is a putative target enzyme for NSAIDs, knowledge of the topography of the enzyme's antiinflammatory drug and prostaglandin binding site could aid in future drug design. This approach may offer distinct advantages over working w
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The Government has rights in this invention pursuant to NIH Grants GM 33464 and NRSA GM 12274, awarded by the Department of Health and Human Services.
Askonas Leslie J.
Penning Trevor M.
Springer David B.
Trustees of the University of Pennsylvania
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