RESUMO
Induction of IFNα in the upper airways via activation of TLR7 represents a novel immunomodulatory approach to the treatment of allergic asthma. Exploration of 8-oxoadenine derivatives bearing saturated oxygen or nitrogen heterocycles in the N-9 substituent has revealed a remarkable selective enhancement in IFNα inducing potency in the nitrogen series. Further potency enhancement was achieved with the novel (S)-pentyloxy substitution at C-2 leading to the selection of GSK2245035 (32) as an intranasal development candidate. In human cell cultures, compound 32 resulted in suppression of Th2 cytokine responses to allergens, while in vivo intranasal administration at very low doses led to local upregulation of TLR7-mediated cytokines (IP-10). Target engagement was confirmed in humans following single intranasal doses of 32 of ≥20 ng, and reproducible pharmacological response was demonstrated following repeat intranasal dosing at weekly intervals.
Assuntos
Adenina/análogos & derivados , Asma/tratamento farmacológico , Descoberta de Drogas , Piperidinas/administração & dosagem , Piperidinas/farmacologia , Receptor 7 Toll-Like/agonistas , Adenina/administração & dosagem , Adenina/química , Adenina/farmacologia , Administração Intranasal , Asma/metabolismo , Relação Dose-Resposta a Droga , Humanos , Estrutura Molecular , Piperidinas/química , Relação Estrutura-AtividadeRESUMO
Enantiopure bromonium ions may be generated from enantiopure bromohydrins and derivatives, they can be trapped with an in situ nucleophile to give enantiomerically pure products.
Assuntos
Álcoois/química , Brometos/química , Brometos/síntese química , EstereoisomerismoRESUMO
Suitably ortho-substituted iodobenzenes act as organocatalysts for the transfer of electrophilic bromine from N-bromosuccinimide to alkenes via the intermediacy of bromoiodinanes.
Assuntos
Alcenos/síntese química , Bromosuccinimida/química , Iodobenzenos/química , Alcenos/química , Catálise , Estrutura Molecular , EstereoisomerismoRESUMO
Bromoiodinanes--conveniently and directly prepared from iodobenzenecarbinols and N-bromosuccinimide, and characterised for the first time crystallographically--act as electrophilic bromine donors.
Assuntos
Brometos/química , Bromo/química , Elétrons , Iodo/química , Cristalografia por Raios X , Modelos Moleculares , Estrutura MolecularRESUMO
The synthesis and alkylation of [4.3.0]-bicyclic lactams, derived from 6-oxopipecolic acid, have been investigated. Alkylation can proceed with predominantly exo-diastereoselectivity, but the efficiency of this process depends on the substitution at the hemiaminal ether system. These products can be readily deprotected to give substituted hydroxymethyl lactams in good yield.