RESUMEN
In the course of a programme aimed at identifying Nurr1/NOT agonists for potential treatment of Parkinson's disease, a few hits from high throughput screening were identified and characterized. A combined optimization pointed to a very narrow and stringent structure activity relationship. A comprehensive program of optimization led to a potent and safe candidate drug displaying neuroprotective and anti-inflammatory activity in several in vitro and in vivo models.
Asunto(s)
Fármacos Neuroprotectores/síntesis química , Fármacos Neuroprotectores/farmacología , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Enfermedad de Parkinson/tratamiento farmacológico , Animales , Línea Celular , Cricetinae , Descubrimiento de Drogas , Regulación de la Expresión Génica/efectos de los fármacos , Proteínas de Homeodominio/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Ratones , Microglía/efectos de los fármacos , Estructura Molecular , Neuronas/efectos de los fármacos , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Ratas , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismoRESUMEN
An in-depth study of the cobalt-catalyzed [2+2+2] cycloaddition between yne-ynamides and nitriles to afford aminopyridines has been carried out. About 30 nitriles exhibiting a broad range of steric demand and electronic properties have been evaluated, some of which open new perspectives in metal-catalyzed arene formation. In particular, the use of [CpCo(CO)(dmfu)] (dmfu=dimethyl fumarate) as a precatalyst made possible the incorporation of electron-deficient nitriles into the pyridine core. Modification of the substitution pattern at the yne-ynamide allows the regioselectivity to be switched toward 3- or 4-aminopyridines. Application of this synthetic methodology to the construction of the aminopyridone framework using a yne-ynamide and an isocyanate was also briefly examined. DFT computations suggest that 3-aminopyridines are formed by formal [4+2] cycloaddition between the nitrile and the intermediate cobaltacyclopentadiene, whereas 4-aminopyridines arise from an insertion pathway.
Asunto(s)
Alquinos/química , Amidas/química , Aminopiridinas/síntesis química , Cobalto/química , Nitrilos/química , Piridonas/síntesis química , Aminopiridinas/química , Catálisis , Ciclización , Estructura Molecular , Piridonas/química , EstereoisomerismoRESUMEN
Bimolecular cobalt-catalyzed [2 + 2 + 2] cycloadditions between yne-ynamides and nitriles afford bicyclic 3- or 4-aminopyridines in up to 100% yield. The high regioselectivity observed depends on the substitution pattern at the starting ynamide. Aminopyridines bearing TMS and Ts groups are efficiently deprotected in an orthogonal fashion.
Asunto(s)
4-Aminopiridina/química , Aminopiridinas/química , Compuestos Bicíclicos Heterocíclicos con Puentes/química , Cobalto/química , Catálisis , Modelos Moleculares , Estructura Molecular , EstereoisomerismoRESUMEN
SL651498 (6-fluoro-9-methyl-2-phenyl-4-(pyrrolidin-1-yl-carbonyl)-2,9-dihydro-1H-pyrido[3,4-b]indol-1-one) was identified as a drug development candidate from a research program designed to discover subtype-selective GABA(A) receptor agonists for the treatment of generalized anxiety disorder and muscle spasms. The drug displays high affinity for rat native GABA(A) receptors containing alpha(1) (K(i) = 6.8 nM) and alpha(2) (K(i) = 12.3 nM) subunits, and weaker affinity for alpha5-containing GABA(A) receptors (K(i) = 117 nM). Studies on recombinant rat GABA(A) receptors confirm these findings and indicate intermediate affinity for the alpha(3)beta(2)gamma(2) subtype. SL651498 behaves as a full agonist at recombinant rat GABA(A) receptors containing alpha(2) and alpha(3) subunits, and as a partial agonist at recombinant GABA(A) receptors expressing alpha(1) and alpha(5) subunits. SL651498 produced anxiolytic-like and skeletal muscle relaxant effects qualitatively similar to those of benzodiazepines (BZs) [minimal effective dose (MED): 1 to 10 mg/kg, i.p. and 3 to 10 mg/kg, p.o.]. However, unlike these latter drugs, SL651498 induced muscle weakness, ataxia or sedation at doses much higher than those having anxiolytic-like activity (MED: 30 to 100 mg/kg, i.p. or p.o.). Moreover, in contrast to BZs, SL651498 did not produce tolerance to its anticonvulsant activity or physical dependence. It was much less active than BZs in potentiating the depressant effects of ethanol or impairing cognitive processes in rodents. The differential profile of SL651498 as compared to BZs may be related to its selective efficacy at the alpha(2)- and alpha(3)-containing GABA(A) receptors. This suggests that selectively targeting GABA(A) receptor subtypes can lead to drugs with increased clinical specificity. SL651498 represents a promising alternative to agents currently used for the treatment of anxiety disorders and muscle spasms without the major side effects seen with classical BZs.