Molecular Pharmacology, Vol 19, 456-462, Copyright © 1981 by the American Society for Pharmacology and Experimental Therapeutics

Inhibition of 15-Hydroxyprostaglandin Dehydrogenase by 9,11-Deoxyprostaglandins in Vitro and in Vivo

¹ Central Research Laboratories, Sankyo Company, Ltd., Tokyo, Japan 140

Fourty-six prostaglandin analogues were studied to determine their ability to inhibit 15-hydroxyprostaglandin dehydrogenase partially purified from swine lung. The inhibition was high in prostaglandin analogues having the following structure: (a) cyclopentane ring with no substituent; (b) hydroxy or keto group at carbon atom 15: (c) lengths of side chains similar to those of prostaglandin: and (d) methylene group between carbon atoms 13 and 14. The most potent inhibitor was rac-13,14-methylene-15-ketoprostanoate, the K_i being 0.14 µM, and its inhibition was noncompetitive with regard to prostaglandin (PG) E₂, the substrate. This compound inhibited [³H]PGE₁ degradation in the soluble fraction of guinea pig lung homogenates. One potent inhibitor, 15-hydroxyprost-13-enoate (9,11-deoxy-PGE₁), was tested for its in vivo effect in anesthetized rats. When PGE₁ was intravenously infused together with 9,11-deoxy-PGE₁, its antilipolytic activity was significantly enhanced. Namely, the blood free fatty acid levels, which had been elevated by norepinephrine injection, were markedly decreased by the infusions of PGE₁ with the inhibitor.