Inhibition of prostaglandin 15-hydroxydehydrogenase by sulphasalazine and a novel series of potent analogues

doi:10.1016/0006-2952(83)90390-8

Biochemical Pharmacology

Volume 32, Issue 19, 1 October 1983, Pages 2863-2871

https://doi.org/10.1016/0006-2952(83)90390-8 Get rights and content

Abstract

The ability of sulphasalazine, its colonic metabolites and various analogues to inhibit prostaglandin inactivation by two purified preparations of type INAD⁺-dependent prostaglandin 15-hydroxydehydrogenase or in various 100,000 g cytosolic supernatants was investigated using PGF_2a as substrate and radio-TLC. Bovine lung and human placental PGDH were inhibited in a dose-dependent and apparently non-competitive manner by sulphasalazine and most of the 26 salazine/sulphasalazine analogues tested, but the potencies of the analogues varied considerably. In a survey of structure-activity effects testing 30 drugs at a fixed dose (50 μM) in six test systems, it was established that only two aromatic rings are needed and that optimal PGDH inhibition requires -CH₂COOH and -OH at positions 1 and 2 in the salicyl C ring system. Homosalazine was thus established as the type compound of a novel series of powerful PGDH inhibitors. Electronegative substituents meta or para in ring B produce compounds with > 150 × inhibitory potency of sulphasalazine, and a significant linear corrlation (r = 0.82, P < 0.002) was found between the inhibitory activity and the Hammett σ substituent Constant in this series of ten homosalazine analogues.

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Inhibition of prostaglandin 15-hydroxydehydrogenase by sulphasalazine and a novel series of potent analogues

Abstract

Eur. J. Pharmac.

Prostaglandins

Biochem. Pharmac.

Lancet

Eur. J. Pharmac.

Br. J. Pharmac.

Br. J. Pharmac.

Agents Actions Supp.