Molecular Pharmacology, Vol 7, 111-115, Copyright © 1971 by the American Society for Pharmacology and Experimental Therapeutics

Analogues of 4-(3,4-Dimethoxybenzyl)-2-imidazolidinone as Potent Inhibitors of Rat Erythrocyte Adenosine Cyclic 3',5'-Phosphate Phosphodiesterase

¹ Hoffmann-La Roche Inc., Research Division, Department of Pharmacology, Nutley, New Jersey 07110

A number of analogues of 4-(3,4-dimethoxybenzyl)-2-imidazolidinone (Ro 7-2956), a hypotensive and lipolytic agent, have been tested for their ability to inhibit rat erythrocyte phosphodiesterase (adenosine 3',5'-cyclic phosphate, adenosine 5'-phosphate phosphohydrolase, EC 3.1.4.c). Elongation of the alkyl group in ether linkage with the oxygen at position 3 increased activity, whereas the reverse was true with the oxygen at position 4. The most potent compound, the 3-butoxy-4-methoxy derivative, was 5000 times more potent than theophylline. Both isomers derived from the asymmetrical carbon of the imidazolidinone ring were quite active, but opening of the ring markedly reduced activity, and addition of a carboxyl group yielded an almost inactive compound. This series introduces a new and potent group of inhibitors of phosphodiesterase which, in addition to their physiological effects, may be useful in probing the inhibitory site of the enzyme.