Abstract
ROCK has been implicated in many diseases ranging from glaucoma to spinal cord injury and is therefore an important target for therapeutic intervention. In this study, we have designed a series of 1-(4-(1H-indazol-5-yl)piperazin-1-yl)-2-hydroxy(or 2-amino) analogs and a series of 1-(4-(1H-indazol-5-yl amino)piperidin-1-yl)-2-hydroxy(or 2-amino) inhibitors of ROCK-II. SR-1459 has IC(50)=13nM versus ROCK-II while the IC(50)s for SR-715 and SR-899 are 80nM and 100nM, respectively. Many of these inhibitors, especially the 2-amino substituted analogs for both series, are modest/potent CYP3A4 inhibitors as well. However, a few of these inhibitors (SR-715 and SR-899) show strong selectivity for ROCK-II over CYP3A4, but the overall potency of the 2-amino analogs (SR-1459) on CYP3A4 and the high clearance and volume of distribution of these compounds makes the in vivo utility of these analogs undesirable.
MeSH terms
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Animals
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme Inhibitors
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Drug Stability
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Humans
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Indazoles / chemistry
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Indazoles / metabolism*
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Indazoles / pharmacokinetics*
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Inhibitory Concentration 50
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Intracellular Signaling Peptides and Proteins / antagonists & inhibitors*
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Pharmaceutical Preparations / metabolism
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Pharmacokinetics
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Piperazines / chemistry
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Piperazines / metabolism
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Piperazines / pharmacokinetics
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Piperidines / chemistry
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Piperidines / metabolism
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Piperidines / pharmacokinetics
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Protein Kinase Inhibitors / metabolism
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Protein Kinase Inhibitors / pharmacokinetics*
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Protein Serine-Threonine Kinases / antagonists & inhibitors*
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Rats
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Structure-Activity Relationship
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rho-Associated Kinases
Substances
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Cytochrome P-450 Enzyme Inhibitors
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Indazoles
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Intracellular Signaling Peptides and Proteins
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Pharmaceutical Preparations
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Piperazines
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Piperidines
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Protein Kinase Inhibitors
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Cytochrome P-450 CYP3A
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CYP3A4 protein, human
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Protein Serine-Threonine Kinases
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rho-Associated Kinases