Discovery of Isoquinolinesulfonamide as a Protein Kinase Inhibitor 1.1

History of Discovery

Chemical compounds incorporating a sulfonamide residue have been synthesized for therapeutic purposes for over 70 years. In the period 19301950, many compounds were patented. Prontosil was produced as an antibacterial agent, and several kinds of sulfonamide derivatives appeared as diuretic agents. Other sulfonylureas were synthesized for different indications and used clinically for diabetes mellitus. However, none of the patents on sulfonamides, as their use as medicines declined, was maintained any more in the period of 1950-1970.

In the latter half of the 1970s, Hidaka et al. brought a new and unexpected focus on certain sulfonamide derivatives (Fig. 1). In 1978, a newly synthesized compound, N-(6-aminohexyl)-5-chloro-1-naphthalene-sulfonamide (W-7) was reported to inhibit contractile response of vascular smooth muscle in concentrations ranging from 1 to 300 mM by affecting actomyosin ATPase activity (Hidaka et al. 1978a). The molecular mechanism of W-7 action was then more thoroughly investigated (Hidaka et al. 1978b; Hidaka et al. 1979). W-7 inhibited the superprecipitation of aorta smooth muscle actomyosin, and the addition of the modulator protein calmodulin (CaM) neutralized, in a dose-dependent fashion, the inhibition of actomyosin super-precipitation by W-7 in a dose-dependent fashion.



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