RESUMO
This article describes the chemical synthesis, ADME and pharmacological properties and early safety pharmacology evaluation of a series of novel Nurr1/NOT agonist. It is meant as a support to an article recently published in Bioorganic and Medicinal chemistry Letters and entitled "Development of a novel NURR1/NOT agonist from hit to lead and candidate for the potential treatment of Parkinson's disease" [1] and presenting the discovery, scope and potential of these new ligands of these nuclear receptors.
RESUMO
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.
Assuntos
Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/farmacologia , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/metabolismo , Doença de Parkinson/tratamento farmacológico , Animais , Linhagem Celular , Cricetinae , Descoberta de Drogas , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Homeodomínio/metabolismo , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Camundongos , Microglia/efeitos dos fármacos , Estrutura Molecular , Neurônios/efeitos dos fármacos , Membro 2 do Grupo A da Subfamília 4 de Receptores Nucleares/genética , Ratos , Receptores X de Retinoides/genética , Receptores X de Retinoides/metabolismoRESUMO
Deacetylation of uridyldiphospho-3-O-(R-hydroxydecanoyl)-N-acetylglucosamine by LpxC is the first committed step in the Pseudomonas aeruginosa biosynthetic pathway to lipid A; homologous enzymes are found widely among Gram-negative bacteria. As an essential enzyme for which no inhibitors have yet been reported, the P. aeruginosa LpxC represents a highly attractive target for a novel antibacterial drug. We synthesized several focused small-molecule libraries, each composed of a variable aromatic ring, one of four heterocyclic/spacer moieties, and a hydroxamic acid and evaluated the LpxC inhibition of these compounds against purified P. aeruginosa enzyme. To ensure that the in vitro assay would be as physiologically relevant as possible, we synthesized a tritiated form of the specific P. aeruginosa glycolipid substrate and measured directly the enzymatically released acetate. Several of our novel compounds, predominantly those having fluorinated substituents on the aromatic ring and an oxazoline as the heterocyclic moiety, demonstrated in vitro IC(50) values less than 1 microM. We now report the synthesis and in vitro evaluation of these P. aeruginosa LpxC inhibitors.
