RESUMEN
TAK-925, a potent, selective, and brain-penetrant orexin 2 receptor (OX2R) agonist, [methyl (2R,3S)-3-((methylsulfonyl)amino)-2-(((cis-4-phenylcyclohexyl)oxy)methyl)piperidine-1-carboxylate, 16], was identified through the optimization of compound 2, which was discovered by a high throughput screening (HTS) campaign. Subcutaneous administration of compound 16 produced wake-promoting effects in mice during the sleep phase. Compound 16 (TAK-925) is being developed for the treatment of narcolepsy and other related disorders.
RESUMEN
This manuscript reports a visible-light-mediated organosulfide catalysis that enables the decarboxylative coupling between simple aliphatic alcohol and tertiary or secondary alkyl carboxylic acid-derived redox active esters to produce a C(sp3)-O-C(sp3) fragment. Results of the coupling using other heteroatom nucleophiles such as water, amides, and thiols are also described.
RESUMEN
A series of benzofuran derivatives with neuroprotective activity in collaboration with IGF-1 was discovered using a newly developed cell-based assay involving primary neural cells prepared from rat hippocampal and cerebral cortical tissues. A structure-activity relationship study identified compound 8 as exhibiting potent activity and brain penetrability. An in vitro pharmacological study demonstrated that although IGF-1 and 8 individually exhibited the neuroprotective effect, the latter acted in collaboration with IGF-1 to enhance neuroprotective activity.
Asunto(s)
Benzofuranos/farmacología , Descubrimiento de Drogas , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Benzofuranos/síntesis química , Benzofuranos/química , Células Cultivadas , Relación Dosis-Respuesta a Droga , Estructura Molecular , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/química , Ratas , Relación Estructura-ActividadRESUMEN
We report herein the discovery and optimization of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one TYK2 inhibitors. High-throughput screening against TYK2 and JAK1-3 provided aminoindazole derivative 1 as a hit compound. Scaffold hopping of the aminoindazole core led to the discovery of 3-amino-1,5-dihydro-4H-pyrazolopyridin-4-one derivative 3 as a novel chemotype of TYK2 inhibitors. Interestingly, initial SAR study suggested that this scaffold could have a vertically flipped binding mode, which prompted us to introduce a substituent at the 7-position as a moiety directed toward the solvent-exposed region. Introduction of a 1-methyl-3-pyrazolyl moiety at the 7-position resulted in a dramatic increase in TYK2 inhibitory activity, and further optimization led to the discovery of 20. Compound 20 inhibited IL-23-induced IL-22 production in a rat PD assay, as well as inhibited IL-23 signaling in human PBMC. Furthermore, 20 showed selectivity for IL-23 signaling inhibition against GM-CSF, demonstrating the unique cytokine selectivity of the novel TYK2 inhibitor.
Asunto(s)
Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , TYK2 Quinasa/antagonistas & inhibidores , Animales , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Ensayos Analíticos de Alto Rendimiento , Humanos , Interleucina-23/farmacología , Interleucinas/biosíntesis , Janus Quinasa 2/antagonistas & inhibidores , Células Jurkat , Masculino , Modelos Moleculares , Monocitos/efectos de los fármacos , Monocitos/enzimología , Inhibidores de Proteínas Quinasas/farmacocinética , Ratas , Ratas Endogámicas Lew , Relación Estructura-Actividad , Interleucina-22RESUMEN
Asymmetric 1,4-addition of arylboronic acids to (E)-methyl 2-cyano-3-arylpropenoates proceeded in the presence of a rhodium catalyst (3 mol %) coordinated with a chiral diene ligand, (R,R)-Ph-bod*, to give high yields of the corresponding methyl 3,3-diaryl-2-cyanopropanoates with high enantioselectivity (up to 99% ee). This catalytic asymmetric transformation was applied to the asymmetric synthesis of (R)-tolterodine.
RESUMEN
[reaction: see text]. Rhodium-catalyzed asymmetric 1,4-addition of arylboronic acids to coumarins proceeded with high enantioselectivity in the presence of a rhodium catalyst (3 mol %) generated from Rh(acac)(C2H4)2 and (R)-Segphos to give the corresponding (R)-4-arylchroman-2-ones in over 99% ee. This asymmetric reaction was applied to the synthesis of (R)-tolterodine.
Asunto(s)
Compuestos de Bencidrilo/síntesis química , Ácidos Borónicos/química , Cumarinas/química , Cresoles/síntesis química , Fenilpropanolamina/síntesis química , Rodio/química , Compuestos de Bencidrilo/análisis , Catálisis , Cresoles/análisis , Estructura Molecular , Fenilpropanolamina/análisis , Estereoisomerismo , Tartrato de TolterodinaRESUMEN
[Reaction: see text] Asymmetric synthesis of diarylmethylamines with high enantioselectivity (95-99% ee) was realized by use of a new C2-symmetric diene ligand, (1R,5R)-2,6-diphenylbicyclo[3.3.1]nona-2,6-diene (Ph-bnd), for the rhodium-catalyzed asymmetric arylation of N-(4-nitrobenzenesulfonyl)arylimines with arylboroxines.
RESUMEN
Asymmetric synthesis of diarylmethylamines with high enantioselectivity (95-99% ee) was realized by use of a new C2-symmetric diene ligand, (1R,4R)-2,5-diphenylbicyclo[2.2.2]octa-2,5-diene (Ph-bod*), for the rhodium-catalyzed asymmetric arylation of N-tosylarylimines with arylboroxines.
RESUMEN
A rhodium-catalyzed asymmetric 1,4-addition reaction has been applied to the synthesis of 2-aryl-4-piperidones. While other conventional nucleophiles fail, organozinc reagents have been successfully utilized for the construction of these useful compounds in very good yield and enantiomeric excess.
Asunto(s)
Piperidonas/síntesis química , Rodio/química , Zinc/química , Catálisis , Indicadores y Reactivos , Compuestos Organometálicos/química , Estereoisomerismo , Taquicininas/antagonistas & inhibidoresRESUMEN
Addition of lithium aryl(tetraisopropoxy)titanates [ArTi(OPr-i)(4)(-)Li(+)] to alpha,beta-unsaturated ketones proceeded with high enantioselectivity (up to 99% ee) in the presence of an excess amount of chlorotrimethylsilane and a rhodium catalyst (3 mol % Rh), generated from [RhCl(C(2)H(4))(2)](2) and (S)-binap, in tetrahydrofuran at 20 degrees C to give high yields of the corresponding silyl enolates as 1,4-addition products. The presence of chlorotrimethylsilane is essential for the 1,4-addition to take place. (31)P NMR spectroscopic studies revealed that the catalytic cycle consists of three transformations, that is, (i) insertion of an enone into arylrhodium species forming (oxa-pi-allyl)rhodium intermediate, (ii) silylation of the (oxa-pi-allyl)rhodium with chlorotrimethylsilane giving silyl enolate and a chloro-rhodium complex, and (iii) transmetalation of aryl group from aryltitanate to the chloro-rhodium regenerating the aryl-rhodium.
RESUMEN
[reaction: see text] The addition of aryltitanate reagents ArTi(OPr-i)4Li to 3-alkynyl-2-en-1-ones in the presence of chlorotrimethylsilane and a rhodium-(R)-segphos as a catalyst proceeded in a 1,6-fashion to give a high yield of axially chiral allenylalkenyl silyl enol ethers with up to 93% ee.
RESUMEN
As a new type of chiral ligand, a C2-symmetric norbornadiene derivative (1R,4R)-2,5-dibenzylbicyclo[2.2.1]hepta-2,5-diene (1) was prepared and used for the rhodium-catalyzed asymmetric addition of organoboron and -tin reagents to alpha,beta-unsaturated ketones, which gave high yields of the 1,4-addition products with up to 99% enantioselectivity.
RESUMEN
Treatment of an (allyl)organosilane with silica gel in refluxing toluene brought about deallylation forming an Si-O-Si bond with the silicon on the silica gel. This Si-O-Si bond formation provides us with a new reliable method for the functionalization of a silica gel surface.
RESUMEN
The addition of aryltitanium triisopropoxide (ArTi(OPr-i )3) to alpha,beta-unsaturated ketones proceeded with high enantioselectivity (94-99.8% ee) in the presence of 3 mol % of [Rh(OH)((S )-binap)]2 in THF at 20 degrees C to give high yields of the titanium enolates as 1,4-addition products. The titanium enolates were converted into silyl enol ethers by treatment with chlorotrimethylsilane and lithium isopropoxide.