5048-44-2Relevant articles and documents
EXTRAHEPATIC DELIVERY
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Paragraph 0566; 0662, (2021/05/15)
One aspect of the present invention relates to a compound comprising an antisense strand which is complementary to a target gene; a sense strand which is complementary to said antisense strand; and one or more lipophilic monomers, containing one or more lipophilic moieties, conjugated to one or more positions on at least one strand, optionally via a linker or carrier. Another aspect of the invention relates to a method of gene silencing, comprising administering to a cell or a subject in need thereof a therapeutically effective amount of the lipophilic monomer-conjugated compound.
A General Acid-Mediated Hydroaminomethylation of Unactivated Alkenes and Alkynes
Kaiser, Daniel,Tona, Veronica,Gon?alves, Carlos R.,Shaaban, Saad,Oppedisano, Alberto,Maulide, Nuno
supporting information, p. 14639 - 14643 (2019/09/17)
In comparison to the extensively studied metal-catalyzed hydroamination reaction, hydroaminomethylation has received significantly less attention despite its considerable potential to streamline amine synthesis. State-of-the-art protocols for hydroaminomethylation of alkenes rely largely on transition-metal catalysis, enabling this transformation only under highly designed and controlled conditions. Here we report a broadly applicable, acid-mediated approach to the hydroaminomethylation of unactivated alkenes and alkynes. This methodology employs cheap, readily available, and bench-stable reactants and affords the desired amines with excellent functional group tolerance and impeccable regioselectivity. The broad scope of this transformation, as well as mechanistic investigations and in situ domino functionalization reactions are reported.
Inhibitors of acyl-CoA:cholesterol O-acyltransferase. Synthesis and pharmacological activity of (±)-2-dodecyl-α-phenyl-N-(2,4,6- trimethoxyphenyl)-2H-tetrazole-5-acetamide and structurally related tetrazole amide derivatives
O'Brien,Sliskovic,Picard,Lee,Purchase II,Roth,White,Anderson,Mueller,Bocan,Bousley,Hamelehle,Homan,Lee,Krause,Reindel,Stanfield,Turluck
, p. 2354 - 2366 (2007/10/03)
A series of tetrazole amide derivatives of (±)-2-dodecyl-α-phenyl-N- (2,4,6-trimethoxyphenyl)-2H-tetrazole-5-acetamide (1) was prepared and evaluated for their ability to inhibit acyl-CoA: cholesterol O- acyltransferase (ACAT) in vitro and to lower plasma total cholesterol in vivo. For this series of compounds, our objective was to systematically replace substituents appended to the amide and tetrazole moieties of 1 with structurally diverse functionalities and assess the effect that these changes have on biological activity. The ensuing structure-activity relationship (SAR) studies identified aryl (7b) and heteroaryl (7f,g) replacements for 2,4,6-trimethoxyphenyl that potently inhibit liver microsomal and macrophage ACAT in vitro and exhibit good cholesterol lowering activity (56-66% decreases in plasma total cholesterol at 30 mg/kg), relative to 1, when compared in the acute rat model of hypercholesterolemia. Replacement of the α-phenyl moiety with electron-withdrawing substituents (13e-h), however, significantly reduced liver microsomal ACAT inhibitory activity (IC50 > 1 μM). This is in contrast to electron-donating substituents (13ij,m-q), which produce IC50 values ranging from 5 to 75 nM in the hepatic microsomal assay. For selected tetrazole amides (1, 7b, 13n,o), reversing the order of substituents appended to the 2- and 5-positions in the tetrazole ring (36a- d), in general, improved macrophage ACAT inhibitory activity and provided excellent cholesterol-lowering activity (ranging from 65% to 77% decreases in plasma total cholesterol at 30 mg/kg) in the acute rat screen. The most potent isomeric pair in this set of unsubstituted methylene derivatives (13n and 36a) caused adrenocortical cell degeneration in guinea pigs treated with these inhibitors. In contrast, adrenal glands taken from guinea pigs treated with the corresponding α-phenyl-substituted analogs (7b and 36c) were essentially unchanged compared to untreated controls. Subsequent evaluation of 7b and 36c in a rabbit bioassay showed that both compounds and/or their metabolites were present in plasma after oral dosing. Unlike 7b and 36c, compound 1 and related 2,4,6-trimethoxyanilides (13j, 30c,d) showed poor oral activity in the rabbit bioassay. Nevertheless, in cholesterol-fed rabbits, both systemically available (7b, 36c) and poorly absorbed inhibitors (1, 36d) were more effective in lowering plasma total cholesterol than the fatty acid amide CI-976.
