Highly potent inhibition of prostaglandin 15-hydroxydehydrogenase in-vitro and of prostaglandin inactivation in perfused lung by the new azobenzene analogue, Ph CL 28A
Berry, C.N.; Hoult, J.R.; Phillips, J.A.; McCarthy, T.M.; Agback, H.
Journal of Pharmacy and Pharmacology 37(9): 622-628
1985
ISSN/ISBN: 0022-3573 PMID: 2867182 Document Number: 251221
The new azobenzene analogue Ph CL 28A (2-hydroxy-5-(3,5-dimethoxycarbonyl-benzoyl)-benzene acetic acid) potently inhibited prostaglandin 15-hydroxydehydrogenase (PGDH) in the nanomolar range in-vitro and inhibited prostaglandin inactivation in rat perfused lung at similar concentrations, and is the most potent PGDH inhibitor yet available. It was synthesized because electronegative substituents in the B ring of homosalazine enhance PGDH inhibitory potency. Ph CL 28A inhibited human placental PGDH non-competitively with regard both to substrate PGF2.alpha. (Ki = 18.7 .+-. 0.9 nM) and the NAD+ cofactor (Ki = 57.6 .+-. 2.9 nM); inhibition was greatly reduced at pH .gtoreq. 8.0. Ph CL 28A hydrolyses spontaneously in alkali (t1/2 at pH 9.0 = 45 h) to the less active dicarboxylic acid (IC50 human placental PGDH 1.6 .mu.M versus 0.028 .mu.M for Ph CL 28A). The new analogue is 1000 .times. more active than the parent compound sulphasalazine from which it derives. The IC50 values for five azobenzene analogues in rat perfused lung (Ph CL 28A = 72 nM) correlated strongly with those obtained using purified PGDH (r = 0.99), suggesting that they inhibit pulmonary prostaglandin degradation at the enzyme step rather than at the hypothetical carrier. The new compound will be a useful probe for PGDH structure and function.