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Steinberg, Mitchell I.; McCall, Eileen; Mest, H.‐J.; Raap, Achim; Wright, Theressa J.

doi:10.1023/a:1009712916873

Cited by 7 publications

(3 citation statements)

References 151 publications

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“…DPI 201‐106 was undergoing clinical trials in the late 1980s. [ 73 ] In HF patients with ischemic or dilated cardiomyopathy, short‐term intravenous administration of DPI 201‐106 increased all indices of contractility without affecting HR or pressure. Moreover, in both categories of patients, positive inotropic activity was accompanied by significant decreases in left ventricular end‐diastolic pressures and other indices of preload.…”

Section: Ion Channel Blockersmentioning

confidence: 99%

“…Substances that slow or remove the inactivation process of cardiac Na + channels are considered in the literature as agents that are able to prolong the effective refractory period (ERP) and increase contractility, thereby offering the potential for use as antiarrhythmic therapy in patients with depressed myocardial contractility. [73,74] DPI 201-106 and other indole derivatives…”

Section: Na + -Channel Activators/modulatorsmentioning

confidence: 99%

“…[79] DPI 201-106 was undergoing clinical trials in the late 1980s. [73] In HF patients with ischemic or dilated cardiomyopathy, short-term being the active enantiomer. [76] Stenzel et al from Beiersdorf AG (Germany) patented a group of positive inotropic DPI 201-106 derivatives 17 with varying substituents in aromatic rings and the structure and size of the saturated nitrogen-containing ring in the linker in 1990.…”

Section: Na + -Channel Activators/modulatorsmentioning

confidence: 99%

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Linked biaromatic compounds as cardioprotective agents

Mokrov

2021

Archiv der Pharmazie

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Cardiovascular diseases (CVDs) are widespread in the modern world, and their number is constantly growing. For a long time, CVDs have been the leading cause of morbidity and mortality worldwide. Drugs for the treatment of CVD have been developed almost since the beginning of the 20th century, and a large number of effective cardioprotective agents of various classes have been created. Nevertheless, the need for the design and development of new safe drugs for the treatment of CVD remains. Literature data indicate that a huge number of cardioprotective agents of various generations and mechanisms correspond to a single generalized pharmacophore model containing two aromatic nuclei linked by a linear linker. In this regard, we put forward a concept for the design of a new generation of cardioprotective agents with a multitarget mechanism of action within the indicated pharmacophore model. This review is devoted to a generalization of the currently known compounds with cardioprotective properties and corresponding to the pharmacophore model of biaromatic compounds linked by a linear linker. Particular attention is paid to the history of the creation of these drugs, approaches to their design, and analysis of the structure-action relationship within each class.

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Section: Ion Channel Blockersmentioning

confidence: 99%

Section: Na + -Channel Activators/modulatorsmentioning

confidence: 99%

Section: Na + -Channel Activators/modulatorsmentioning

confidence: 99%

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Linked biaromatic compounds as cardioprotective agents

Mokrov

2021

Archiv der Pharmazie

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Tanimura¹,

Mishima²,

Steinberg

et al. 2000

Cardiovascular Drugs and Therapy

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The use of positive inotropic agents, such as sympathomimetics and phosphodiesterase inhibitors, in heart failure (HF) is limited by proarrhythmic and positive chronotropic effects. In the present study, we compared the hemodynamic effects of intravenous LY366634 (LY), a Na+ channel enhancer, with dobutamine (DOB), in eight dogs with HF produced by intracoronary microembolizations. We also determined whether intravenous LY has synergistic effects when combined with digoxin. After baseline measurements, infusion of DOB was initiated at a dose of 2 micrograms/kg/min and increased until an increase of heart rate (HR) 30% of baseline or ventricular arrhythmias developed. Once hemodynamics returned to baseline, LY was infused at a dose of 2 micrograms/kg/min and increased until the LV fractional area of shortening (FAS), determined echocardiographically, reached a similar level as with DOB. Both drugs increased FAS equivalently compared to baseline (DOB, 24 +/- 3 to 47 +/- 2; LY, 27 +/- 2 to 46 +/- 2%). DOB increased HR from 78 +/- 4 min-1 at baseline to 107 +/- 7 min-1 at maximal dose (p < 0.05) and provoked serious arrhythmias in one dog. In contrast, LY infusion did not increase HR (82 +/- 7 vs. 80 +/- 8 min-1) or elicit arrhythmias. After 1 week of oral digoxin, dogs were infused again with LY. A lower dose of LY was needed to achieve the same increase in FAS compared to LY alone, but this was not statistically significant. The combination of LY with digoxin did not increase HR or evoke arrhythmias. We conclude that in dogs with HF, intravenous LY improves LV function to the same extent as DOB without increasing HR or evoking ventricular arrhythmias. The combination of LY with digoxin elicits a safe positive inotropic response.

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