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Inotropic Agents. Synthesis and Structure-Activity Relationships of New Milrinone Related cAMP PDE III Inhibitors

Inotropic Agents. Synthesis and Structure-Activity Relationships of New Milrinone Related cAMP PDE III Inhibitors

P Fossa, R Boggia, E Lo Presti, L Mosti, P Dorigo, M Floreani

Farmaco. Aug-Sep 1997;52(8-9):523-30.

PMID: 9507660

Abstract:

The synthesis of 6-substituted 5-acyl-1,2-dihydro-2-oxo-3-pyridinecarbonitriles 1b,c, 1,2,5,6,7,8-hexahydro-2,5-dioxo-3-quinolinecarbonitriles 1d-g and esters of 5-cyano-1,6-dihydro-2-methyl-6-oxo-3-pyridinecarboxylic acid 2b-e is described. In the case of 1e and 1f, a careful elucidation of the reaction mechanism is discussed. As milrinone analogues, the above compounds were tested on contractile activity and frequency rate of spontaneously beating atria from reserpine-treated guinea pigs. The methyl and the benzyl esters 2b and 2e showed an appreciable positive inotropic activity when compared to milrinone. A fitting study with the DISCO (Distance Comparison) model has been carried out on 2e. This modeling approach allowed for the improvement of the pharmacophoric requirements for a better interaction with the cAMP-specific PDE (PDE III), thought to be the final biological target of these cardiotonic agents.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP62749262	Amrinone Related Compound C		62749-26-2	Price

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