331-41-9Relevant academic research and scientific papers
Structure-Activity Studies of Bis-O-Arylglycolamides: Inhibitors of the Integrated Stress Response
Hearn, Brian R.,Jaishankar, Priyadarshini,Sidrauski, Carmela,Tsai, Jordan C.,Vedantham, Punitha,Fontaine, Shaun D.,Walter, Peter,Renslo, Adam R.
, p. 870 - 880 (2016)
The integrated stress response comprises multiple signaling pathways for detecting and responding to cellular stress that converge at a single event - the phosphorylation of Ser51 on the α-subunit of eukaryotic translation initiation factor 2 (eIF2α). Phosphorylation of eIF2α (eIF2α-P) results in attenuation of global protein synthesis via the inhibitory effects of eIF2α-P on eIF2B, the guanine exchange factor (GEF) for eIF2. Herein we describe structure-activity relationship (SAR) studies of bis-O-arylglycolamides, first-in-class integrated stress response inhibitors (ISRIB). ISRIB analogues make cells insensitive to the effects of eIF2α-P by activating the GEF activity of eIF2B and allowing global protein synthesis to proceed with residual unphosphorylated eIF2α. The SAR studies described herein support the proposed pharmacology of ISRIB analogues as binding across a symmetrical protein-protein interface formed between protein subunits of the dimeric eIF2B heteropentamer. Stress management: Herein we describe structure-activity studies of bis-O-arylglycolamides, first-in-class Integrated Stress Response InhiBitors (ISRIB). ISRIB analogues make cells insensitive to the effects of eIF2α phosphorylation by activating eIF2B, the guanine exchange factor for eIF2. ISRIB analogues are thought to bind and stabilize a protein-protein interface in the dimeric form of the eIF2B heteropentameric protein complex.
CHEMICAL COMPOUNDS
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Page/Page column 117, (2020/02/06)
The invention is directed to substituted carbon-linked bicycloalkane derivatives. Specifically, the invention is directed to compounds according to Formula (X): (X) wherein C', D', L2', L3', R1', R2', R3', R4', R5', R6', R7', R8', z1', z2', z3', z4', z5', z6', X1, and X2 are as defined herein; or a salt thereof including a pharmaceutically acceptable salt thereof. The compounds of the invention are inhibitors of the ATF4 pathway and can be useful in the treatment of cancer, pre-cancerous syndromes and diseases associated with activated unfolded protein response pathways, such as Alzheimer's disease, spinal cord injury, traumatic brain injury, ischemic stroke, stroke, diabetes, Parkinson disease, Huntington's disease, Creutzfeldt-Jakob Disease, and related prion diseases, progressive supranuclear palsy, amyotrophic lateral sclerosis, myocardial infarction, cardiovascular disease, inflammation, fibrosis, chronic and acute diseases of the liver, chronic and acute diseases of the lung, chronic and acute diseases of the kidney, chronic traumatic encephalopathy (CTE), neurodegeneration, dementia, cognitive impairment, atherosclerosis, ocular diseases, neurological disorders, pain, arrhythmias, in organ transplantation and in the transportation of organs for transplantation. Accordingly, the invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting the ATF4 pathway and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
INHIBITORS OF INTEGRATED STRESS RESPONSE PATHWAY
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Paragraph 2545; 2546, (2019/06/20)
The present disclosure relates generally to therapeutic agents that may be useful as inhibitors of Integrated Stress Response (ISR) pathway.
CHEMICAL COMPOUNDS AS ATF4 PATHWAY INHIBITORS
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Page/Page column 212-213, (2019/01/06)
The invention is directed to substituted bridged cycloalkane derivatives. Specifically, the invention is directed to compounds according to Formula (IIIQ): wherein X6', a, b, C8', D8', L82', L83', R81', R82', R83', R84', R85', R86', z82', z84', z85', and z86' are as defined herein; or salts thereof. The compounds of the invention are inhibitors of the ATF4 pathway. Accordingly, invention is further directed to pharmaceutical compositions comprising a compound of the invention. The invention is still further directed to methods of inhibiting the ATF4 pathway and treatment of disorders associated therewith using a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
