Cardiotonic agents. 7. Prodrug derivatives of 4-ethyl-1,3-dihydro-5-[4-(2-methyl-1H-imidazol-1-yl)benzoyl]-2H-imidazol-2-one

• Published in: Journal of medicinal chemistry 1992-04, Vol.35 (7), p.1267-1272
• Main Authors: Shaw, Kenneth J, Erhardt, Paul W, Hagedom, Alfred A, Pease, Cynthia A, Ingebretsen, William R, Wiggins, Jay R
• Format: Article
• Language: English
• Subjects: Animals; Biological Availability; Cardiotonic Agents - chemical synthesis; Cardiotonic Agents - pharmacokinetics; Chromatography, High Pressure Liquid; Dogs; Drug Stability; Half-Life; Humans; Hydrogen-Ion Concentration; Imidazoles - chemistry; Imidazoles - pharmacokinetics; Imidazoles - pharmacology; Molecular Structure; Prodrugs - chemical synthesis; Prodrugs - pharmacokinetics; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00085a014

The cardiotonic agent 4-ethyl-1,3-dihydro-5-4-(2-methyl-1H-imidazol-1-yl)benzoyl]-2H- imidazol-2-one (1) was found to have low bioavailability when administered orally to rats and dogs. A series of N-acyl derivatives, an underutilized prodrug of acidic NH compounds, has been synthesized and tested for their ability to improve the oral bioavailability of 1. Reaction of the monosodium salt of 1 with various anhydrides afforded the N-1 monoacylimidazolones with surprisingly high regioselectivity. In addition to the prodrugs, acylation of 1 with propionic or phenylacetic anhydride led to the novel 3H-pyrrolo[1,2-c]imidazole-3,5(2H)-diones 6. The prodrugs showed a significant increase in the partition coefficients with a minor decrease in the aqueous solubility. The benzoyl derivative 4b exhibited the highest stability in both pH 1.5 and 7.4 buffer solutions. Further evaluation of 4b showed rapid conversion to 1 in canine plasma (t1/2 = 38 min), and human plasma (t1/2 = 10 min). Oral studies indicated that the bioavailability of 4b was increased to greater than 75% (compared to less than 20% for 1), and hemodynamic studies demonstrated that the selective inotropic profile of 1 was retained.