Highly potent inhibition of prostaglandin 15-hydroxydehydrogenase in-vitro and of prostaglandin inactivation in perfused lung by the new azobenzene analogue, Ph CL 28A.
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 greater than or equal to 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 microM versus 0.028 microM for Ph CL 28A). The new analogue is 1000 X 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.
Berry
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Hoult
J R
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Phillips
J A
JA
McCarthy
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TM
Agback
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D000818:Animals; D001391:Azo Compounds / Q000494:pharmacology*; D003106:Colon / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D015237:Dinoprost; D006911:Hydroxyprostaglandin Dehydrogenases / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D007700:Kinetics; D008168:Lung / Q000201:enzymology / Q000378:metabolism*; D008297:Male; D008861:Microsomes / Q000378:metabolism; D011453:Prostaglandins / Q000378:metabolism*; D011460:Prostaglandins F / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D012669:Seminal Vesicles / Q000378:metabolism; D012756:Sheep
D001391:Azo Compounds; D011453:Prostaglandins; D011460:Prostaglandins F; C047498:Ph CL 28A; D015237:Dinoprost; D006911:Hydroxyprostaglandin Dehydrogenases; C035859:15-hydroxyprostaglandin dehydrogenase