Antihypertensive compounds with potent protein kinases inhibitory activity

A new indorocarbazole antibiotic SF2370 has been found in the culture broth of Actinomadura sp.; it has also been found to have the activities of antihypertension and diuresis. Derivatives of SF2370, NA0344, NA0345 and NA0346, when injected (0.1-1 mg/kg i.v.) significantly lowered the blood pressure of anesthetized normotensive rats and showed a long lasting antihypertensive action. In the case of p.o. administration to conscious restrained SHRs, measurement of blood pressure by the plethysmographic method indicated that 10 mg/kg of the compounds was enough to lower the blood pressure; the antihypertensive activities were found to remain more than 12 hrs after oral administration. By studying of the mode of antihypertensive action, these compounds dose dependently relaxed the isolated aortic preparation contracted by norepinephrine. In addition, it was found that protein kinase C activity of mice brain was inhibited by the compounds; the IC50 values were in the range of 0.062-0.20 microM. Moreover, a superprecipitation of actomyosin from smooth muscle of chicken gizzard was inhibited by the compounds, having an IC50 values of 0.31-0.72 microM.