- Development of a manufacturing process for an HCV protease inhibitor candidate molecule
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The scale-up of a prototype HCV protease inhibitor (1) from gram scale in the laboratory to kilogram scale in the pilot plant is described. Key features of the optimization included the synthesis of bulk quantities of exomethylene proline intermediate 6, separation of the diastereomers of spirocycle 2 without chromatography, isolation of the precursor to 1 to purge byproducts that might raise genotoxic structural alerts, and purification of an amorphous drug substance via a crystalline acetic acid solvate.
- Littler, Benjamin J.,Aizenberg, Michael,Ambhaikar, Narendra B.,Blythe, Todd A.,Curran, Timothy T.,Dvornikovs, Vadims,Jung, Young C.,Jurkauskas, Valdas,Lee, Elaine C.,Looker, Adam R.,Luong, Hoa,Martinot, Theodore A.,Miller, David B.,Neubert-Langille, Bobbianna J.,Otten, Pieter A.,Rose, Peter J.,Ruggiero, Piero L.
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Read Online
- Pd-Catalyzed ipso, meta-Dimethylation of ortho-Substituted Iodoarenes via a Base-Controlled C-H Activation Cascade with Dimethyl Carbonate as the Methyl Source
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A methyl group can have a profound impact on the pharmacological properties of organic molecules. Hence, developing methylation methods and methylating reagents is essential in medicinal chemistry. We report a palladium-catalyzed dimethylation reaction of ortho-substituted iodoarenes using dimethyl carbonate as a methyl source. In the presence of K2CO3 as a base, iodoarenes are dimethylated at the ipso- and meta-positions of the iodo group, which represents a novel strategy for meta-C-H methylation. With KOAc as the base, subsequent oxidative C(sp3)-H/C(sp3)-H coupling occurs; in this case, the overall transformation achieves triple C-H activation to form three new C-C bonds. These reactions allow expedient access to 2,6-dimethylated phenols, 2,3-dihydrobenzofurans, and indanes, which are ubiquitous structural motifs and essential synthetic intermediates of biologically and pharmacologically active compounds.
- Wu, Zhuo,Wei, Feng,Wan, Bin,Zhang, Yanghui
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supporting information
p. 4524 - 4530
(2021/05/04)
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- Synthesis, antiepileptic effects, and structure-activity relationships of α-asarone derivatives: In vitro and in vivo neuroprotective effect of selected derivatives
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In the present study, we compared the antiepileptic effects of α-asarone derivatives to explore their structure-activity relationships using the PTZ-induced seizure model. Our research revealed that electron-donating methoxy groups in the 3,4,5-position on phenyl ring increased antiepileptic potency but the placement of other groups at different positions decreased activity. Besides, in allyl moiety, the optimal activity was reached with either an allyl or a 1-butenyl group in conjugation with the benzene ring. The compounds 5 and 19 exerted better neuroprotective effects against epilepsy in vitro (cell) and in vivo (mouse) models. This study provides valuable data for further exploration and application of these compounds as potential anti-seizure medicines.
- Zhang, Jian,Mu, Keman,Yang, Peng,Feng, Xinqian,Zhang, Di,Fan, Xiangyu,Wang, Qiantao,Mao, Shengjun
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- Potent hemithioindigo-based antimitotics photocontrol the microtubule cytoskeleton in cellulo
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Background: Hemithioindigo is a promising molecular photoswitch that has only recently been applied as a photoswitchable pharmacophore for control over bioactivity in cellulo. Uniquely, in contrast to other photoswitches that have been applied to biology,
- Ahlfeld, Julia,Bingham, Rebekkah,Ermer, Franziska,Kraus, Yvonne,Lutter, Ferdinand H.,Sailer, Alexander,Thorn-Seshold, Oliver
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supporting information
p. 125 - 134
(2020/03/27)
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- Semi-quantitative models for identifying potent and selective transthyretin amyloidogenesis inhibitors
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Rate-limiting dissociation of the tetrameric protein transthyretin (TTR), followed by monomer misfolding and misassembly, appears to cause degenerative diseases in humans known as the transthyretin amyloidoses, based on human genetic, biochemical and pharmacologic evidence. Small molecules that bind to the generally unoccupied thyroxine binding pockets in the native TTR tetramer kinetically stabilize the tetramer, slowing subunit dissociation proportional to the extent that the molecules stabilize the native state over the dissociative transition state—thereby inhibiting amyloidogenesis. Herein, we use previously reported structure-activity relationship data to develop two semi-quantitative algorithms for identifying the structures of potent and selective transthyretin kinetic stabilizers/amyloidogenesis inhibitors. The viability of these prediction algorithms, in particular the more robust in silico docking model, is perhaps best validated by the clinical success of tafamidis, the first-in-class drug approved in Europe, Japan, South America, and elsewhere for treating transthyretin aggregation-associated familial amyloid polyneuropathy. Tafamidis is also being evaluated in a fully-enrolled placebo-controlled clinical trial for its efficacy against TTR cardiomyopathy. These prediction algorithms will be useful for identifying second generation TTR kinetic stabilizers, should these be needed to ameliorate the central nervous system or ophthalmologic pathology caused by TTR aggregation in organs not accessed by oral tafamidis administration.
- Connelly, Stephen,Mortenson, David E.,Choi, Sungwook,Wilson, Ian A.,Powers, Evan T.,Kelly, Jeffery W.,Johnson, Steven M.
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supporting information
p. 3441 - 3449
(2017/07/07)
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- Photocatalytic synthesis of dihydrobenzofurans by oxidative [3+2] cycloaddition of phenols
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We report a protocol for oxidative [3+2] cycloadditions of phenols and alkenes applicable to the modular synthesis of a large family of dihydrobenzofuran natural products. Visible-light-activated transition metal photocatalysis enables the use of ammonium persulfate as an easily handled benign terminal oxidant. The broad range of organic substrates that are readily oxidized by photoredox catalysis suggests that this strategy may be applicable to a variety of useful oxidative transformations.
- Blum, Travis R.,Zhu, Ye,Nordeen, Sarah A.,Yoon, Tehshik P.
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supporting information
p. 11056 - 11059
(2015/03/30)
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- Indolinone based LRRK2 kinase inhibitors with a key hydrogen bond
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The most prevalent leucine-rich repeat kinase 2 (LRRK2) mutation G2019S is associated with Parkinson's disease (PD). It enhances kinase activity and has been identified in both familial and sporadic cases. Kinase activity was reported to be required for LRRK2 mutants to exert their toxic effects. Hence LRRK2 kinase inhibition may be a promising therapeutic target for PD. Here we report on the discovery and characterization of indolinone based LRRK2 inhibitors. Indolinone 15b, the most potent and selective inhibitor of the present series, is characterized by an IC50of 15 nM against wild-type LRRK2 and 10 nM against the LRRK2 G2019S mutant, respectively. Compound 15b was further evaluated in a kinase panel including 46 human protein kinases and in a zebrafish embryo phenotype assay, which enabled toxicity determination in whole organisms.
- G?ring, Stefan,Taymans, Jean-Marc,Baekelandt, Veerle,Schmidt, Boris
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supporting information
p. 4630 - 4637
(2015/02/05)
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- Toward optimization of the linker substructure common to transthyretin amyloidogenesis inhibitors using biochemical and structural studies
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To develop potent and highly selective transthyretin (TTR) amyloidogenesis inhibitors, it is useful to systematically optimize the three substructural elements that compose a typical TTR kinetic stabilizer: the two aryl rings and the linker joining them. Herein, we evaluated 40 bisaryl molecules based on 10 unique linker substructures to determine how these linkages influence inhibitor potency and selectivity. These linkers connect one unsubstituted aromatic ring to either a 3,5-X2 or a 3,5-X2-4-OH phenyl substructure (X = Br or CH3). Coconsideration of amyloid inhibition and ex vivo plasma TTR binding selectivity data reveal that direct connection of the two aryls or linkage through nonpolar E-olefin or -CH2CH2- substructures generates the most potent and selective TTR amyloidogenesis inhibitors exhibiting minimal undesirable binding to the thyroid hormone nuclear receptor or the COX-1 enzyme. Five high-resolution TTR·inhibitor crystal structures (1.4-1.8 A?) provide insight into why such linkers afford inhibitors with greater potency and selectivity.
- Johnson, Steven M.,Connelly, Stephen,Wilson, Ian A.,Kelly, Jeffery W.
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supporting information; experimental part
p. 6348 - 6358
(2009/12/03)
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