Imidazo[1,2-a]pyridines. I. Synthesis and inotropic activity of new 5-imidazo[1,2-a]pyridinyl-2(1H)-pyridinone derivatives.
A series of 1,2-dihydro-5-imidazo[1,2-a]pyridinyl-2(1H)-pyridonones was synthesized and evaluated for positive inotropic activity, 1,2-Dihydro-5-imidazo[1,2-a]pyridin-6-yl-6-methyl-2- oxo-3-pyridinecarbonitrile (11a) hydrochloride monohydrate (E-1020) was found to be a potent and selective inhibitor of phosphodiesterase III and a long-acting, potent, orally active positive inotropic agent. Additional imidazo[1,2-a]pyridin-2-yl (3a), -3-yl (16), -7-yl (20) and -8-yl (24a) compounds were also prepared. Altering the pyridine substitution from the 2-position to the 6-position produced a 2-fold increase in the i.v. cardiotonic potency (ED50) from 52 to 23 micrograms/kg, while substitution at the 3-, 7- or 8-position reduced potency. In the 2-positional isomers, introduction of halogen groups enhanced the activity and 3-chloro-1,2-dihydro-5-(6-fluoroimidazo[1,2-a] pyridin-2-yl)-6-methyl-2(1H)-pyridinone (3u) was the most potent (i.v. ED50 11 micrograms/kg) in this series. E-1020 is presently under development for the treatment of congestive heart failure.
Eisai Tsukuba Research Laboratories, Ibaraki, Japan.
M
M
Yamanaka
K
K
Miyake
S
S
Suda
H
H
Ohhara
T
T
Ogawa
D000818:Animals; D002316:Cardiotonic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D002316:Cardiotonic Agents; D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; D011728:Pyridones