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9 results on '"Parkhill Eric Q"'

1. Discovery of potent and selective inhibitors of calmodulin-dependent kinase II (CaMKII)

Author

Koltun, Dmitry O., Parkhill, Eric Q., Kalla, Rao, Perry, Thao D., Elzein, Elfatih, Li, Xiaofen, Simonovich, Scott P., Ziebenhaus, Christopher, Hansen, Timothy R., Marchand, Bruno, Hung, WaiLok K., Lagpacan, Leanna, Hung, Magdeleine, Aoyama, Ron G., Murray, Bernard P., Perry, Jason K., Somoza, John R., Villaseñor, Armando G., Pagratis, Nikos, and Zablocki, Jeff A.

Published
2018
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2. Discovery of triazolopyridinone GS-462808, a late sodium current inhibitor (Late INai) of the cardiac Nav1.5 channel with improved efficacy and potency relative to ranolazine

Author

Koltun, Dmitry O., Parkhill, Eric Q., Elzein, Elfatih, Kobayashi, Tetsuya, Jiang, Robert H., Li, Xiaofen, Perry, Thao D., Avila, Belem, Wang, Wei-Qun, Hirakawa, Ryoko, Smith-Maxwell, Catherine, Wu, Lin, Dhalla, Arvinder K., Rajamani, Sridharan, Mollova, Nevena, Stafford, Brian, Tang, Jennifer, Belardinelli, Luiz, and Zablocki, Jeff A.

Published
2016
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3. Discovery of triazolopyridine GS-458967, a late sodium current inhibitor (Late INai) of the cardiac NaV 1.5 channel with improved efficacy and potency relative to ranolazine

Author

Koltun, Dmitry O., Parkhill, Eric Q., Elzein, Elfatih, Kobayashi, Tetsuya, Notte, Gregory T., Kalla, Rao, Jiang, Robert H., Li, Xiaofen, Perry, Thao D., Avila, Belem, Wang, Wei-Qun, Smith-Maxwell, Catherine, Dhalla, Arvinder K., Rajamani, Sridharan, Stafford, Brian, Tang, Jennifer, Mollova, Nevena, Belardinelli, Luiz, and Zablocki, Jeff A.

Published
2016
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7. Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties.

Author

Zablocki, Jeff A., Elzein, Elfatih, Li, Xiaofen, Koltun, Dmitry O., Parkhill, Eric Q., Tetsuya Kobayashi, Martinez, Ruben, Corkey, Britton, Haibo Jiang, Perry, Thao, Kalla, Rao, Notte, Gregory T., Saunders, Oliver, Graupe, Michael, Lu, Yafan, Venkataramani, Chandru, Guerrero, Juan, Perry, Jason, Osier, Mark, and Strickley, Robert

Published
2016
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8. Using Patchxpress to Screen Blockers of the Cardiac Sodium Channel (Nav1.5) for Effects on Late INA, Peak INA, and Channel Kinetics

Author

Luiz Belardinelli, Elfatih Elzein, Kobayashi Tetsuya, Josephine Salcedo, Cathy Smith-Maxwell, Parkhill Eric Q, Rao Kalla, Hilary Zou, John C. Shryock, Robert Jiang, Dmitry Koltun, Xiaofen Li, Jeff Zablocki, Kim W. Chan, and Malcolm McGregor

Subjects
Quinidine, biology, Sodium channel, Voltage clamp, Tefluthrin, Biophysics, Nav1.5, Pharmacology, chemistry.chemical_compound, chemistry, Mexiletine, medicine, biology.protein, Patch clamp, Flecainide, medicine.drug
Abstract

The Nav1.5 channel is responsible for the upstroke of the action potential in cardiac myocytes. Congenital mutations in hNav1.5 have been shown to impair fast inactivation, leading to an increase in persistent sodium current (late INa) and LQT3. Growing evidence suggests that an increase in late INa can contribute to the pathogenesis of several cardiac diseases. With the goal of finding small molecules that selectively target cardiac late INa over peak INa and have rapid unbinding kinetics, we developed three novel assays on PatchXpress using HEK-293 cells stably expressing hNav1.5. The first assay measures block of late INa generated by tefluthrin, a pyrethroid that impairs fast inactivation. We chose tefluthrin over another late INa activator, the sea anemone toxin ATX-II, because with tefluthrin late INa reaches steady state faster and more reliably. Importantly, block obtained with tefluthrin and ATX-II is usually similar. The second assay measures tonic and use-dependent block of peak INa stimulated at 0.1 Hz and 3 Hz, respectively. To reduce voltage clamp errors on PatchXpress due to large inward peak currents and access resistance, we used 50% series resistance compensation and reduced Na+ in the extracellular solution to 20 mM. The third assay is designed to determine the rate at which compounds dissociate from the channel and is calculated from the time-course of the decrease in peak INa when the stimulation frequency is reduced from 10 to 1 Hz. All three assays on PatchXpress were validated by comparing IC50s or off-rates for several standard Nav1.5 blockers (eg. flecainide, mexiletine, quinidine and lidocaine) to those obtained from manual patch clamp. IC50s agree within two-fold and off-rate rankings are identical.

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9. Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late I Na i), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties.

Author

Zablocki JA, Elzein E, Li X, Koltun DO, Parkhill EQ, Kobayashi T, Martinez R, Corkey B, Jiang H, Perry T, Kalla R, Notte GT, Saunders O, Graupe M, Lu Y, Venkataramani C, Guerrero J, Perry J, Osier M, Strickley R, Liu G, Wang WQ, Hu L, Li XJ, El-Bizri N, Hirakawa R, Kahlig K, Xie C, Li CH, Dhalla AK, Rajamani S, Mollova N, Soohoo D, Lepist EI, Murray B, Rhodes G, Belardinelli L, and Desai MC

Abstract

Late sodium current (late I Na ) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na v 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late I Na , is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late I Na inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC 50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I Na inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

Published
2016
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