Synthesis and in‐vitro inotropic evaluation of 2‐(4‐substitutedbenzyl‐1,4‐diazepan‐1‐yl)‐N‐(4,5‐dihydro‐1‐phenyl‐[1,2,4]triazolo[4,3‐a]quinolin‐7‐yl)acetamides

Abstract

We describe the synthesis and positive inotropic evaluation of a series of 2-(4-substitutedbenzyl-1,4-diazepan-1-yl)-N-(4,5-dihydro-1-phenyl-[1,2,4]triazolo[4,3-a]quinolin-7-yl)acetamides by measuring left atrial stroke volume in preparations of isolated rabbit-heart. Several compounds were developed from, and showed favorable activities compared with the standard drug milrinone. Compound 5o was the most potent with an increased stroke volume of 9.17 ± 0.14% (milrinone 2.47 ± 0.08%) at 3 × 10⁻⁵ M in our in-vitro study. The chronotropic effects of those compounds having inotropic effects were also evaluated.

Synthesis and Biological Evaluation of [1,2,4]Triazolo[3,4‐a]phthalazine and Tetrazolo[5,1‐a]phthalazine Derivatives Bearing Substituted Benzylpiperazine Moieties as Positive Inotropic Agents

“…The introduction of triazole ring at the first and second position of the 3,4‐dihydro‐2(1H)‐quinolinone, as in PHR0007, resulted in a remarkable increase in the biological activity (Figure ) , as indicated by the phosphodiesterase III inhibition . In a summary of our previous work associated with the effects of modifications to PHR0007 , we hypothesized that the triazole and piperazine rings were essential to the observed higher levels of affinity for the receptor and consequently enhanced the positive inotropic activity. In the current report, we describe the further modifications that we have made to PHR0007.…”