- Discovery of Ziresovir as a Potent, Selective, and Orally Bioavailable Respiratory Syncytial Virus Fusion Protein Inhibitor
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Ziresovir (RO-0529, AK0529) is reported here for the first time as a promising respiratory syncytial virus (RSV) fusion (F) protein inhibitor that currently is in phase 2 clinical trials. This article describes the process of RO-0529 as a potent, selective, and orally bioavailable RSV F protein inhibitor and highlights the in vitro and in vivo anti-RSV activities and pharmacokinetics in animal species. RO-0529 demonstrates single-digit nM EC50 potency against laboratory strains, as well as clinical isolates of RSV in cellular assays, and more than one log viral load reduction in BALB/c mouse model of RSV viral infection. RO-0529 was proven to be a specific RSV F protein inhibitor by identification of drug resistant mutations of D486N, D489V, and D489Y in RSV F protein and the inhibition of RSV F protein-induced cell-cell fusion in cellular assays.
- Zheng, Xiufang,Gao, Lu,Wang, Lisha,Liang, Chungen,Wang, Baoxia,Liu, Yongfu,Feng, Song,Zhang, Bo,Zhou, Mingwei,Yu, Xin,Xiang, Kunlun,Chen, Li,Guo, Tao,Shen, Hong C.,Zou, Gang,Wu, Jim Zhen,Yun, Hongying
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p. 6315 - 6329
(2019/07/09)
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- Novel carvedilol analogues that suppress store-overload-induced Ca 2+ release
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Carvedilol is a uniquely effective drug for the treatment of cardiac arrhythmias in patients with heart failure. This activity is in part because of its ability to inhibit store-overload-induced calcium release (SOICR) through the RyR2 channel. We describe the synthesis, characterization, and bioassay of ca. 100 compounds based on the carvedilol motif to identify features that correlate with and optimize SOICR inhibition. A single-cell bioassay was employed on the basis of the RyR2-R4496C mutant HEK-293 cell line in which calcium release from the endoplasmic reticulum through the defective channel was measured. IC50 values for SOICR inhibition were thus obtained. The compounds investigated contained modifications to the three principal subunits of carvedilol, including the carbazole and catechol moieties, as well as the linker chain containing the β-amino alcohol functionality. The SAR results indicate that significant alterations are tolerated in each of the three subunits.
- Smith, Chris D.,Wang, Aixia,Vembaiyan, Kannan,Zhang, Jingqun,Xie, Cuihong,Zhou, Qiang,Wu, Guogen,Chen, S. R. Wayne,Back, Thomas G.
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p. 8626 - 8655
(2013/12/04)
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- Agents for treating disorders involving modulation of ryanodine receptors
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The present invention relates to 1,4-benzothiazepine derivatives and their use to treat conditions, disorders and diseases associated with ryanodine receptors (RyRs) that regulate calcium channel functioning in cells. The invention also discloses pharmaceutical compositions comprising the compounds and uses thereof to treat diseases and conditions associated with RyRs, in particular cardiac, musculoskeletal and central nervous system (CNS) disorders.
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- COMPOUNDS AND METHODS FOR MODULATING ACTIVITY OF CALCIUM RELEASE CHANNELS
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The present teachings provide compounds of Formulae I and II: and and pharmaceutically acceptable salts, hydrates, complexes, esters, and prodrugs thereof, wherein R1, R1', R2, R2', R3, R3', and X are as defined herein. The present teachings also provide methods of making the compounds of formulae I and II, and methods of treating RyR-associated conditions, disorders, and diseases that include administering a therapeutically effective amount of a compound of formula I or II to a subject in need thereof. In addition, the present teachings relate to methods of reducing the open probability of a ryanodine receptor, and methods of reducing Ca2+ release across a ryanodine receptor (e.g., into the cytoplasm of a cell), by contacting a compound of formula I or II with a ryanodine receptor.
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Page/Page column 42
(2010/11/04)
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- PROCESS FOR PREPARING BENZOTHIAZEPINES FROM GAMMA-AMINOALKYLBENZENES
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The invention provides a process for preparing a 2,3,4,5-tetrahydro[1,4]benzothiazepine of formula: by reacting a [2-(acylaminoethyl)thio]arene of formula with an aldehyde or a multimer thereof, and with an acid. The invention also provides for first reac
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Page/Page column 13; 14
(2009/09/26)
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- Novel agents for preventing and treating disorders involving modulation of the RyR receptors
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The present invention provides novel compounds of Formula I and salts, hydrates, solvates, complexes, and prodrugs thereof. The present invention further provides methods for synthesizing compounds of Formula I. The invention additionally provides pharmaceutical compositions comprising the compounds of Formula I and methods of using the pharmaceutical compositions of Formula I to treat and prevent disorders and diseases associated with the RyR receptors that regulate calcium channel functioning in cells. Such disorders and diseases include, by way of example only, cardiac disorders and diseases, skeletal muscular disorders and diseases, cognitive disorders and diseases, malignant hyperthermia, diabetes, and sudden infant death syndrome. Cardiac disorder and diseases include, but are not limited to, irregular heartbeat disorders and diseases; exercise-induced irregular heartbeat disorders and diseases; sudden cardiac death; exercise-induced sudden cardiac death; congestive heart failure; chronic obstructive pulmonary disease; and high blood pressure. Irregular heartbeat disorders and diseases include and exercise-induced irregular heartbeat disorders and diseases include, but are not limited to, atrial and ventricular arrhythmia; atrial and ventricular fibrillation; atrial and ventricular tachyarrhythmia; atrial and ventricular tachycardia; catecholaminergic polymorphic ventricular tachycardia (CPVT); and exercise-induced variants thereof. Skeletal muscular disorder and diseases include, but are not limited to, skeletal muscle fatigue, exercise-induced skeletal muscle fatigue, muscular dystrophy, bladder disorders, and incontinence. Cognitive disorders and diseases include, but are not limited to, Alzheimer's Disease, forms of memory loss, and age-dependent memory loss.
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Page/Page column 34
(2008/06/13)
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- Novel anti-arrhythmic and heart failure drugs that target the leak in the ryanodine receptor (RyR2) and uses thereof
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The present invention provides methods for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject. The present invention further provides methods for treating and preventing atrial and ventricular cardiac arrhythmias, heart failure, and exercise-induced sudden cardiac death in a subject. Additionally, the present invention provides use of JTV-519 in a method for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject who has, or is a candidate for, atrial fibrillation. Also provided are uses of 1,4-benzothiazepine derivatives in methods for treating and preventing atrial and ventricular cardiac arrhythmias and heart failure in a subject, and for preventing exercise-induced sudden cardiac death. The present invention also provides methods for identifying agents for use in treating and preventing atrial fibrillation and heart failure, and agents identified by these methods.
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Page/Page column 37
(2008/06/13)
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- Compounds and methods for treating and preventing exercise-induced cardiac arrhythmias
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The present invention provides a method for limiting or preventing a decrease in the level of RyR2-bound FKBP12.6 in a subject, a method for treating or preventing exercise-induced cardiac arrhythmia in a subject, and a method for preventing exercise-induced sudden cardiac death in a subject. Also provided are uses of JTV-519 in these methods. The present invention further provides methods for identifying agents for use in preventing exercise-induced sudden cardiac death, as well as agents identified by such methods. Also provided are methods for preventing exercise-induced sudden cardiac death by administering these agents. Additionally, the present invention provides methods for synthesizing JTV-519, radio-labeled JTV-519, and 1,4-benzothiazepine intermediates and derivatives.
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- 1,4-benzothiazepine derivatives
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An object of the invention is to provide compounds having a myocardial KD (Kinetic cell death)-inhibiting effect without being accompanied by a cardiodepressant effect. A 1,4-benzothiazepine derivative represented by the following Formula [I]: STR1 wherei
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