ABSTRACT
The synthesis and pharmacological activity of a new series of 5a,7,8,8a-tetrahydro-4H,6H-pyrrolo[3,4-b][1,2,3]triazolo[1,5-d][1,4]oxazine derivatives as potent sigma-1 receptor (σ1R) ligands are reported. A lead optimization program aimed at improving the aqueous solubility of parent racemic nonpolar derivatives led to the identification of several σ1R antagonists with a good absorption, distribution, metabolism, and excretion in vitro profile, no off-target affinities, and characterized by a low basic pKa (around 5) that correlates with high exposure levels in rodents. Two compounds displaying a differential brain-to-plasma ratio distribution profile, 12lR and 12qS, exhibited a good analgesic profile and were selected as preclinical candidates for the treatment of pain.
Subject(s)
Analgesics/chemistry , Receptors, sigma/antagonists & inhibitors , Triazoles/chemistry , Analgesics/metabolism , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Cell Membrane Permeability/drug effects , Disease Models, Animal , Female , Half-Life , Humans , Ligands , Male , Mice , Microsomes, Liver/metabolism , Pain/drug therapy , Rats , Rats, Wistar , Receptors, sigma/metabolism , Structure-Activity Relationship , Triazoles/metabolism , Triazoles/pharmacology , Triazoles/therapeutic use , Sigma-1 ReceptorABSTRACT
The synthesis and pharmacological activity of a new series of bicyclic diazepinones with dual activity toward the α2δ-1 subunit of voltage-gated calcium channels (Cavα2δ-1) and the norepinephrine transporter (NET) are reported. Exploration of the positions amenable for substitution on a nonaminoacidic Cavα2δ-1 scaffold allowed the identification of favorable positions for the attachment of NET pharmacophores. Among the patterns explored, attachment of the 2-ethylamino-9-methyl-6-phenyl-6,7,8,9-tetrahydro-5H-pyrimido[4,5-e][1,4]diazepin-5-one framework to the meta-position of the phenyl ring of the 3-methylamino-1-phenylpropoxy and 3-methylamino-1-thiophenylpropoxy moieties provided dual compounds with excellent NET functionality. Alternative bicyclic frameworks were also explored, and some lead molecules were identified, which showed a balanced dual profile and exhibited good ADMET properties.
Subject(s)
Azepines/pharmacology , Calcium Channels/metabolism , Heterocyclic Compounds, 2-Ring/pharmacology , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Animals , Azepines/chemical synthesis , Azepines/metabolism , CHO Cells , Cricetulus , HEK293 Cells , Heterocyclic Compounds, 2-Ring/chemical synthesis , Heterocyclic Compounds, 2-Ring/metabolism , Humans , Ligands , Molecular Docking Simulation , Molecular Structure , Protein Binding , Structure-Activity RelationshipABSTRACT
The synthesis of novel tricyclic 1,2,3-triazoles starting from cyclic epoxides via the sequential azidolysis, propargylation and 1,3-dipolar cycloaddition is described. Derivatization by N-arylation reaction and the synthesis of enantiomerically pure compounds is also reported. Some of these compounds exhibit significant affinity for the sigma-1 receptor.
ABSTRACT
A new functional polymer where proline is bonded to polystyrene through a 1,2,3-triazole linker depicts characteristics targeted for an artificial aldolase. In spite of the hydrophobicity of the polymer backbone, the resin swells in water with building of an aqueous microenvironment. This property, arising from the formation of a hydrogen-bond network connecting the proline and 1,2,3-triazole fragments, is translated into a very high catalytic activity and enantioselectivity toward direct aldol reactions in water.
Subject(s)
Fructose-Bisphosphate Aldolase/chemical synthesis , Triazoles/chemistry , Molecular Structure , Polystyrenes/chemistry , Proline/chemistry , Solvents/chemistry , Stereoisomerism , Water/chemistryABSTRACT
The first catalytic enantioselective alpha-aminoxylation of aldehydes and ketones using an insoluble, polymer-supported organocatalyst (1) derived from trans-4-hydroxyproline is reported (ee: 96-99%). Reaction rates in the aminoxylation of cyclic ketones with 1 are higher than those reported with l-proline. The insoluble nature of 1 simplifies workup conditions and allows catalyst recycling without an apparent decrease in enantioselectivity or yield.
Subject(s)
Aldehydes/chemistry , Ketones/chemistry , Polymers/chemistry , Aldehydes/chemical synthesis , Amination , Catalysis , Cyclohexanones/chemical synthesis , Cyclohexanones/chemistry , Ketones/chemical synthesis , Molecular Structure , Nitrogen/chemistry , Oxidation-Reduction , Oxygen/chemistry , Proline/chemistry , StereoisomerismABSTRACT
Alkynyl-functionalized amino alcohols have been covalently supported on azidomethylpolystyrene resins with different levels of functionalization through Cu(I)-catalyzed 1,3-dipolar cycloadditions ("click chemistry"). The resulting 1,2,3-triazole-substituted resins, characterized by different levels of ligand loading and, depending on the nature of the alkynyl-functionalized amino alcohol, the presence of a one-carbon, four-carbon, or eight-carbon linear spacer, have been tested as catalysts in the enantioselective phenyl transfer from zinc to aldehydes. High catalytic activities and enantioselectivities (up to 82% ee) have been recorded. The influence of structural characteristics of the resin on enantioselectivity are discussed, and the limitations in enantiocontrol inherent to the use of a 1,2,3-triazole linker have been rationalized with the help of DFT calculations on model systems.
ABSTRACT
4-Hhydroxyproline has been anchored to a polystyrene resin through click chemistry, and the resulting catalyst has been successfully applied to the direct aldol reaction in water. The high hydrophobicity of the resin and the presence of water are key to ensuring high stereoselectivity, whereas yield can be increased by using catalytic amounts of DiMePEG. This effect has been further demonstrated by the inefficiency of a homogeneous, more polar analogue.
ABSTRACT
In situ ATR-FTIR monitoring has allowed the direct study of the effect of additives (trioctylphosphine oxide [TOPO] and oleic acid) on the kinetics and rate of the thermal decomposition of dicobalt octacarbonyl leading to the formation of colloidal cobalt nanoparticles (CoCNPs). The study has shown that additives usually considered as simple surfactants influence the rate and kinetics of the decomposition of dicobalt octacarbonyl. Several of the initial intermediates connecting Co2(CO)8 with CoCNPs have been identified, and a tentative mechanism for the formation of the colloidal nanoparticles has been proposed.
ABSTRACT
Con el fin de hacer una valoración ordenada y sistemática de la patología urológica de nuestros niños y de uniformar criterios en el personal médico de nuestra institución, el Servicio de Urología del Hospital Nacional de Niños presenta su protocolo de estudio de la hematuria
