119830-47-6Relevant academic research and scientific papers
Small Molecule Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Inhibitors: Hit to Lead Optimization of Systemic Agents
Londregan, Allyn T.,Wei, Liuqing,Xiao, Jun,Lintner, Nathanael G.,Petersen, Donna,Dullea, Robert G.,McClure, Kim F.,Bolt, Michael W.,Warmus, Joseph S.,Coffey, Steven B.,Limberakis, Chris,Genovino, Julien,Thuma, Benjamin A.,Hesp, Kevin D.,Aspnes, Gary E.,Reidich, Benjamin,Salatto, Christopher T.,Chabot, Jeffrey R.,Cate, Jamie H.D.,Liras, Spiros,Piotrowski, David W.
, p. 5704 - 5718 (2018)
The optimization of a new class of small molecule PCSK9 mRNA translation inhibitors is described. The potency, physicochemical properties, and off-target pharmacology associated with the hit compound (1) were improved by changes to two regions of the molecule. The last step in the synthesis of the congested amide center was enabled by three different routes. Subtle structural changes yielded significant changes in pharmacology and off-target margins. These efforts led to the identification of 7l and 7n with overall profiles suitable for in vivo evaluation. In a 14-day toxicology study, 7l demonstrated an improved safety profile vs lead 7f. We hypothesize that the improved safety profile is related to diminished binding of 7l to nontranslating ribosomes and an apparent improvement in transcript selectivity due to the lower strength of 7l stalling of off-target proteins.
Compounds with neuroprotective effect, and preparation method and application thereof
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Paragraph 0179-0182, (2021/06/13)
The invention relates to compounds with a neuroprotective effect, and a preparation method and application thereof. Specifically, the compounds disclosed by the invention have a structure as shown in a formula I, and the definitions of all groups and subs
Tuning activation and self-immolative properties of the bioorthogonal alkene-azide click-and-release strategy
Dadhwal, Sumit,Fairhall, Jessica M.,Gamble, Allan B.,Hook, Sarah,Murayasu, Madoka
supporting information, p. 4754 - 4762 (2020/07/13)
We report on a series of 4-azidobenzyloxy-substituted self-immolative linkers which undergo [3 + 2]-cycloaddition (click reaction) with functionalized trans-cyclooctenes (TCOs) at second-order rate constants in the range of 0.017 to 4.9 M-1 s-1. The choice of 4-azidobenzyloxy-substituted linker and the TCO play a critical role in the rate of all click-and-release steps, which includes the [3 + 2]-cycloaddition and subsequent degradation pathway of the triazoline to an aniline that undergoes 1,6- or 1,8-self-immolation of the phenol. We demonstrate that reacting a 4-azido-2,3,5,6-tetrafluorobenzyloxy-linker with a highly strained TCO (d-TCO) gives, to the best of our knowledge, the fastest TCO-strained alkene-azide click reaction to date (4.9 M-1 s-1), but with one caveat; release of phenol via 1,6-self-immolation is extremely slow. A methyl substituent attached to the benzyl carbon of this analogue maintains the rapid click-reaction rate, but has the added benefit of enabling the release of the phenol within hours. In an aqueous solvent at reagent concentrations in the micromolar range a maximium release was observed after 48 hours; ≈65 and ≈78percent of phenol released depending on the TCO used. The new suite of linkers and their combination with TCOs of varying structure add to the toolbox of bioorthogonal click-and-release reactions. This journal is
JAK1 SELECTIVE KINASE INHIBITOR
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Page/Page column 46; 92-93, (2020/10/28)
Disclosed herein are compounds of Formula (I), and pharmaceutically acceptable salts thereof, that are useful as JAK kinase inhibitors. Also disclosed are pharmaceutical compositions comprising one or more compounds of Formula (I), and methods of using such compounds or compositions to treat respiratory conditions (e.g., asthma or COPD).
CARBOXAMIDES AS MODULATORS OF SODIUM CHANNELS
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Paragraph 001807; 001808, (2019/01/30)
Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.
SUBSTITUTED BICYCLIC AZA-HETEROCYCLES AND ANALOGUES AS SIRTUIN MODULATORS
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Paragraph 0578; 0579, (2017/04/04)
Provided herein are novel substituted bicyclic aza-heterocycle sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
PYRROLCARBOXAMIDE DERIVATIVES FOR THE INHBITION OF ERK5
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Page/Page column 138, (2016/04/09)
The invention provides compounds of formula (I) or a tautomer, stereoisomer, N-oxide, pharmaceutically acceptable salt or solvate thereof. The compounds are useful for the prophylaxis or treatment of a disease state or condition mediated by ERK5, in particular cancers.
NEW BICYCLIC DERIVATIVES HAVING BETA2 ADRENERGIC AGONIST AND M3 MUSCARINIC ANTAGONIST ACTIVITIES
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Page/Page column 68-69, (2016/04/20)
The present invention relates to novel compounds having β2 adrenergic agonist and M3 muscarinic antagonist dual activity, to pharmaceutical compositions containing them, to the process for their preparation and to their use in respiratory therapies.
SUBSTITUTED AMIDE COMPOUNDS
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Paragraph 0336; 0337, (2014/10/29)
The present invention is directed at substituted amide compounds, pharmaceutical compositions containing such compounds and the use of such compounds to reduce plasma lipid levels, such as LDL-cholesterol and triglycerides and accordingly to treat diseases which are exacerbated by high levels of LDL-cholesterol and triglycerides, such as atherosclerosis and cardiovascular diseases, in mammals, including humans.
Highly efficient one-pot amination of carboxylate-substituted nitrogen-containing heteroaryl chlorides via Staudinger reaction
Kandalkar, Sachin R.,Kaduskar, Rahul D.,Ramaiah, Parimi Atchuta,Barawkar, Dinesh A.,Bhuniya, Debnath,Deshpande, Anil M.
supporting information, p. 414 - 418 (2013/02/23)
An efficient one-pot method for the synthesis of tert-butyl 6-aminonicotinate (5) is described. The key transformation involves displacement of the chloro group in tert-butyl 6-chloronicotinate (2) with azide followed by a Staudinger reaction. The scope of this methodology is further extended for the synthesis of a series of carboxylate-substituted heteroaryl amines. In particular, we synthesized tert-butyl carboxylate-substituted amino-pyridine, -pyridazine, and -pyrazine. In addition to one-pot conversion, short reaction time, simplicity of operation, ease of purification, and good yields are the key advantages of this methodology.
