Vol. 282, Issue 1, 236-242, 1997

Structure-Activity Relationships of Spontaneous Nitric Oxide Releasers, FK409 and its Derivatives

Shinichi Fukuyama, Yoshimi Hirasawa, Yasuko Kato , Mie Nishio, Mitsuko Ohno, Shigetaka Nishino, Kazuhiro Maeda, Masayuki Kato and Yasuhiro Kita

Analytical Research Laboratories (S.F.), New Drug Research Laboratories (Y.H., Y.K., M.N., M.O., S.N., K.M., M.K., Y.K.), Fujisawa Pharmaceutical Co., Ltd., 1-6, 2-chome, Kashima, Yodogawa-ku, Osaka 532, Japan

(±)-(E)-4-Ethyl-2-[(E)-hydroxyimino] - 5 - nitro-3-hexenamide (FK409) shows both potent in vitro vasorelaxant and antiplatelet activities via nitric oxide (NO) generated spontaneously from the compound. In this study, we measured spontaneous NO-releasing rates of a series of FK409 derivatives, of which chain lengths or substituents were systematically modified, in sodium-phosphate buffer solution at pH 7.4. Furthermore, we studied their in vitro antiplatelet and vasorelaxant effects to evaluate relationships between spontaneous NO-releasing activities of FK409 analogs and their biological activities. FK409 derivatives were found to possess different spontaneous NO-releasing rates and biological activities according to their structural modification. In addition, these studies revealed a close correlation between NO-releasing rates of FK409 derivatives and their in vitro antiplatelet activities in human platelet-rich plasma, whereas the in vitro vasorelaxant activities of these compounds in isolated rat aorta did not correlate with the rates of NO liberation. The vasorelaxant effects were supposed to be affected by the structural properties of FK409 derivatives as well as their NO-releasing abilities.