Y27632

Y-27632, a pyridine derivative, represents a chemical class distinct from the H inhibitors described above. It has a Ki of 140 nM for Rho kinase and 25 ^M for PKA (Table 1) (Ishizaki et al. 2000) and is ATP competitive, like the H inhibitors (Ikenoya et al. 2002; Trauger et al. 2002). Y-27623 is a widely used Rho kinase inhibitor and several effects could be observed in vitro and in vivo (for review see Ishizaki et al. 2000; Narumiya et al. 2000). It prevents phosphorylation of focal adhesion kinase and paxillin (Sinnett-Smith et al. 2001), inhibits the migration of rat MM1 hepatoma cancer cells (Itoh et al.

Y-27B32 Y-27632

Fig. 6 Binding of Y-27632 to PKA to the ATP binding site. Electron density is displayed at 2 s. (Breitenlechner et al. 2003)

Y-27B32 Y-27632

Fig. 6 Binding of Y-27632 to PKA to the ATP binding site. Electron density is displayed at 2 s. (Breitenlechner et al. 2003)

1999), and leads to smooth muscle contraction and normalization of blood pressure in rats (Uehata et al. 1997). A pyridine ring is connected by an amide to a saturated para-aminoethyl cyclohexane ring. The pyridine similarly occupies the adenine subsite and with the canonical H-bond contacts to the hinge region the Val123 amide group (Fig. 6). The cyclohexane is situated in the ribose subsite. A hydrogen bond is formed from the terminal aminoethyl group to the carbonyl oxygen of Thr51. As the cyclohexane moiety can bind in two slightly different orientations, alternatively, hydrogen bonds from the terminal aminoethyl group to the sidechains of Asp171 and Asp184 are possible too.

The selectivity of Y-27632 for Rho kinase over PKA is 200-fold, a property not immediately rationalized by the structure. It seems, however, likely that the Leu49Ile exchange can enhance hydrophobic interactions. At the same time, the exchange Thr183Ala in Rho kinase offers a wider pocket and greater freedom for the inhibitor to optimize binding interactions.

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