PMID: 3761304Oct 1, 1986Paper

Dihydropyridazinone cardiotonics: the discovery and inotropic activity of 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H -indol-2- one

Journal of Medicinal Chemistry
D W RobertsonJ S Hayes

Abstract

We discovered that 6 (N-[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]acetamide) is a potent positive inotrope in dogs, and we have prepared several lactam analogues of this agent. These included 16 (1,3-dihydro-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-indol-2-one), 32 (the analogous quinolin-2-one), and 37 (the analogous benzazepin-2-one). The inotropic ED50's of these compounds were 24, 3.3, and 5.2 micrograms/kg, respectively, after iv administration to pentobarbital-anesthetized dogs. Compound 20 (LY195115, 1,3-dihydro-3,3-dimethyl-5-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)-2H-i ndol-2- one), the geminal dimethyl analogue of 16, was 3.5-fold more potent than 16 when administered iv (ED50 = 6.8 micrograms/kg). However, the most profound effect of the geminal alkyl substitution was on oral activity. The approximate ED50's of 20 and 16 after oral administration to conscious dogs were 25 and 400 micrograms/kg, respectively. The increase in contractility produced by 25 micrograms/kg of 20 was maximally sustained in excess of 8 h. Thus, 20 is one of the most potent and long-acting oral inotropes described to date.

Citations

Jan 1, 1991·Pharmacology & Therapeutics·W J Thompson
Sep 1, 1987·Toxicology Letters·G E Sandusky, J R Means
Sep 30, 1999·Life Sciences·S PierettiA Galli
Dec 1, 1988·Xenobiotica; the Fate of Foreign Compounds in Biological Systems·J R Bernstein, R B Franklin
Jan 29, 2011·Journal of Enzyme Inhibition and Medicinal Chemistry·Asif HusainAftab Ahmad
Feb 7, 2006·European Journal of Pharmacology·Shiou-Chi CherngTz-Chong Chou
Jul 18, 2008·Journal of Medicinal Chemistry·Thomas E RawsonAndrea G Cochran
Jan 1, 1991·Life Sciences·P W Erhardt, Y L Chou
Jan 5, 1996·Journal of Medicinal Chemistry·H R HowardJ Morrone

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