119830-47-6Relevant articles and documents
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.
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
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.