Cyclic nucleotide phosphodiesterase inhibition by imidazopyridines: analogues of sulmazole and isomazole as inhibitors of the cGMP specific phosphodiesterase.
The synthesis and phosphodiesterase (PDE) inhibitory profile of a series of imidazopyridines, including sulmazole and isomazole, on separated PDE isoenzymes are described. The results show that both sulmazole and isomazole are weak inhibitors of PDE III, and their inotropic activity is unlikely to be due to PDE III inhibition alone. Surprisingly, both compounds were found to be significant inhibitors of the cGMP specific isoenzyme, PDE V, and a series of simple 2-substituted phenylimidazo[4,5-b]pyridines have been made to investigate the SAR of PDE activity. This has been shown to be sensitive to chain length, polarity, and the nature of the heteroatom linking group. Potent PDE V inhibitors, many of which are also significant inhibitors of PDE IV, have been identified.
SmithKline Beecham Pharmaceuticals, Frythe, Welwyn, Hertfordshire, U.K.
W J
WJ
Coates
B
B
Connolly
D
D
Dhanak
S T
ST
Flynn
A
A
Worby
D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
D007093:Imidazoles; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D015106:3',5'-Cyclic-GMP Phosphodiesterases; C029758:sulmazole