Discovery of Potent and Selective Urea-Based ROCK Inhibitors and Their Effects on Intraocular Pressure in Rats

Yin, Yan; Cameron, Michael D.; Lin, Li; Khan, S. A.; Schröter, Thomas; Grant, Wayne; Pocas, Jennifer; Chen, Yen Ting; Schürer, Stephan C.; Pachori, Alok S.; LoGrasso, Philip V.; Feng, Yangbo

doi:10.1021/ml1000382

Cited by 39 publications

(60 citation statements)

References 18 publications

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“…To assess the drugability of these bis -aryl urea based Limk inhibitors, a few potent, selective, and membrane permeable compounds were further evaluated in in vitro and in vivo drug metabolism and pharmacokinetics (DMPK) studies. 41, 46, 50, 52–55 …”

Section: Resultsmentioning

confidence: 99%

“…41, 53 Thus, compound 18w was applied to the right eyes of an elevated IOP rat model (initial IOP was ~ 28 mmHg) using a dose of 50 μg (20 μL drop of a 0.25% solution). As shown in Figure 7, significant decreases in IOP were detected at 4 h, slightly weakened at 7 h, and IOP returning to baseline at 24 h as compared to the vehicle.…”

Section: Resultsmentioning

confidence: 99%

“…Detailed procedures for these assays have been described in previous publications (ref. 41–42, 46, 48–50, and 52–55 ), and were also provided in Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

“…41, 42 Compound 1 had low Limk inhibition in counter-screen studies (IC 50 > 10 μM). However, SAR investigation revealed that replacement of the hinge-binding moiety pyrazole in 1 with a 4-yl-pyrrolopyrimidine (compound 2 ) significantly decreased its ROCK-II affinity (ROCK-II IC 50 = 188 nM of 2 vs. 2 nM of 1 ).…”

Section: Introductionmentioning

confidence: 98%

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Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors

Yin

Zheng²,

Eid³

et al. 2015

J. Med. Chem.

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The discovery/optimization of bis-aryl ureas as Limk inhibitors to obtain high potency and selectivity, and appropriate pharmacokinetic properties through systematic SAR studies is reported. Docking studies supported the observed SAR. Optimized Limk inhibitors had high biochemical potency (IC50 < 25 nM), excellent selectivity against ROCK and JNK kinases (> 400-fold), potent inhibition of cofilin phosphorylation in A7r5,PC-3, and CEM-SS T cells (IC50 < 1 μM), and good in vitro and in vivo pharmacokinetic properties. In the profiling against a panel of 61 kinases, compound 18b at 1 μM inhibited only Limk1 and STK16 with ≥ 80% inhibition. Compounds 18b and 18f were highly efficient in inhibiting cell-invasion/migration in PC-3 cells. In addition, compound 18w was demonstrated to be effective on reducing intraocular pressure (IOP) on rat eyes. Taken together, these data demonstrated that we had developed a novel class of bis-aryl urea derived potent and selective Limk inhibitors.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…Detailed procedures for these assays have been described in previous publications (ref. 41–42, 46, 48–50, and 52–55 ), and were also provided in Supporting Information.…”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors

Yin

Zheng²,

Eid³

et al. 2015

J. Med. Chem.

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“…Human carbonic anhydrase (EC, 4.2.1.1., CA) is a metalloenzyme containing the Zn +2 ion associated with glaucoma, a sight-threatening optic neuropathic disease 1,2 . Glaucoma is caused by the elevation of the intraocular pressure which leads to the destruction of optic nerve cells and the consequent deterioration of eyesight 3,4 .…”

Section: Introductionmentioning

confidence: 99%

Inhibitory effect of novel pyrazole carboxamide derivatives on human carbonic anhydrase enzyme

Şen

Alım

Duran

et al. 2012

Journal of Enzyme Inhibition and Medicinal Chemistry

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In silico prediction of ROCK II inhibitors by different classification approaches

Luo

et al. 2017

Mol Divers

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ROCK II is an important pharmacological target linked to central nervous system disorders such as Alzheimer's disease. The purpose of this research is to generate ROCK II inhibitor prediction models by machine learning approaches. Firstly, four sets of descriptors were calculated with MOE 2010 and PaDEL-Descriptor, and optimized by F-score and linear forward selection methods. In addition, four classification algorithms were used to initially build 16 classifiers with k-nearest neighbors [Formula: see text], naïve Bayes, Random forest, and support vector machine. Furthermore, three sets of structural fingerprint descriptors were introduced to enhance the predictive capacity of classifiers, which were assessed with fivefold cross-validation, test set validation and external test set validation. The best two models, MFK + MACCS and MLR + SubFP, have both MCC values of 0.925 for external test set. After that, a privileged substructure analysis was performed to reveal common chemical features of ROCK II inhibitors. Finally, binding modes were analyzed to identify relationships between molecular descriptors and activity, while main interactions were revealed by comparing the docking interaction of the most potent and the weakest ROCK II inhibitors. To the best of our knowledge, this is the first report on ROCK II inhibitors utilizing machine learning approaches that provides a new method for discovering novel ROCK II inhibitors.

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Discovery of Potent and Selective Urea-Based ROCK Inhibitors and Their Effects on Intraocular Pressure in Rats

Cited by 39 publications

References 18 publications

Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors

Bis-aryl Urea Derivatives as Potent and Selective LIM Kinase (Limk) Inhibitors

Inhibitory effect of novel pyrazole carboxamide derivatives on human carbonic anhydrase enzyme

In silico prediction of ROCK II inhibitors by different classification approaches

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