A structurally novel inhibitor of cGMP phosphodiesterase with vasodilator activity.
A novel, potent, competitive inhibitor of smooth muscle cGMP phosphodiesterase is described (Compound I, [4-[2-n-butyl-5-chloro-1-(2- chlorobenzyl)imidazolyl]methyl] acetate). The compound is highly selective for inhibiting cGMP phosphodiesterase compared with cAMP phosphodiesterase. Compound I inhibits the contraction of smooth muscle in response to a variety of agonists in the same concentration range to that which inhibits the enzyme. Compound I produced a dose-related reduction in the pressor responses to angiotensin II infusion while not inhibiting the responses to bolus doses of angiotensin II. Two structural analogues of Compound I which did not inhibit cGMP phosphodiesterase failed to inhibit smooth muscle contraction in vitro and did not affect angiotensin II pressor responses in vivo. We propose a mechanism to account for the effects of a cGMP phosphodiesterase inhibitor on smooth muscle contraction in vitro and in vivo.
Booth
R F
RF
Searle Research and Development, High Wycombe, Buckinghamshire, U.K.
Lunt
D O
DO
Lad
N
N
Buckham
S P
SP
Oswald
S
S
Clough
D P
DP
Floyd
C D
CD
Dickens
J
J
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors; D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000804:Angiotensin II / Q000037:antagonists & inhibitors; D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000201:enzymology*; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains; D014665:Vasodilator Agents / Q000494:pharmacology*
D007093:Imidazoles; D014665:Vasodilator Agents; D000804:Angiotensin II; C066464:(4-(2-n-butyl-5-chloro-1-(2-chlorobenzyl)imidazolyl)methyl) acetate; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D015106:3',5'-Cyclic-GMP Phosphodiesterases