Abstract
Inhibitors of Rho kinase (ROCK) have potential therapeutic applicability in a wide range of diseases, such as hypertension, stroke, asthma and glaucoma. In a previous article, we described the lead discovery of DL0805, a new ROCK I inhibitor, showing potent inhibitory activity (IC50 6.7 μM). Herein, we present the lead optimization of compound DL0805, resulting in the discovery of 24- and 39-fold more-active analogues 4a (IC50 0.27 μM) and 4b (IC50 0.17 μM), among other active analogues. Moreover, ex-vivo studies demonstrated that 4a and 4b exhibited comparable vasorelaxant activity to the approved drug fasudil in rat aortic rings. The research of a preliminary structure–activity relationship (SAR) indicated that the target compounds containing a β-proline moiety have improved activity against ROCK I relative to analogues bearing an α-proline moiety, and among the series of the derivatives with a β-proline-derived indazole scaffold, the inhibitory activity of the target compounds with a benzyl substituent is superior to those with a benzoyl substituent.
Highlights
Arterial hypertension is a long-term medical condition in which the blood pressure in the arteries is persistently elevated
Previous literature literature had had disclosed disclosed the the development development of ROCK II inhibitors inhibitors with with an an indazole indazole scaffold scaffold attached to a rigid aromatic heterocycle linking structure (I, II, III)
These attached to a rigid aromatic heterocycle linking structure (I, II, III) (Figure 1) [32,33,34]. These studies studies highlighted the importance of the we we report report the the design, design, highlighted the importance of the indazole indazole for for ROCK
Summary
Arterial hypertension is a long-term medical condition in which the blood pressure in the arteries is persistently elevated. Accumulating evidence shows that the activity or is associated with various diseases, including hypertension [4], including stroke [5], dysregulation of expression. Glaucoma [10,11,12], which indicates that is a potential novel hypertension [4], stroke [5], asthma [6,7], cancer [8,9] and glaucoma [10,11,12], which indicatestarget that for drug is development. Previous literature literature had had disclosed disclosed the the development development of ROCK II inhibitors inhibitors with with an an indazole indazole scaffold scaffold attached to a rigid aromatic heterocycle linking structure (I, II, III).
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