In vitro: SR-3677 had an IC50 of ~3 nM in enzyme and cell based assays and had an off-target hit rate of 1.4% against 353 kinases, and inhibited only 3 out of 70 nonkinase enzymes and receptors. Pharmacology studies showed that SR-3677 was efficacious in both, increasing ex vivo aqueous humor outflow in porcine eyes and inhibiting myosin light chain phosphorylation. SR-3677 inhibited only three adrenergic receptors: α1a, α1b, and α2a with 53%, 68%, and 76% inhibition, respectively, at 3 ?M inhibitor concentration, which indicates IC50 values in the 1 ?M range or ~300 times higher than the IC50 against ROCK-II in cell-based assays. In vivo: Continuous exposure of 25 ?M SR-3677 increases the outflow facility by 60% at 1 h perfusion, increasing to 70-80% for the 2-5 h time points (p < 0.01). This 70-80% increase in outflow is the maximal response that can be attained and is achieved at doses 2-4-fold lower than needed for Y-27632, a well studied ROCK inhibitor.TM tissue derived from the eyes perfused with 25 ?M SR-3677 shows a very faint band for p-MLC suggesting greater than 90% inhibition of Rho kinase in the TM tissue at this dose.
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of Compound A used for a mouse (20 mg/kg) to a dose based on the BSA for a rat, multiply 20 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for Compound A of 10 mg/kg.
|Solubility||10mM in DMSO|
Discovery of substituted 4-(pyrazol-4-yl)-phenylbenzodioxane-2-carboxamides as potent and highly selective Rho kinase (ROCK-II) inhibitors.
Feng Y, et al. J Med Chem. 2008 Nov 13;51(21):6642-5. PMID: 18834107.
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