RESUMO
Phosphoinositide 3-kinase (PI3Kγ) is a drug target that has been implicated in the treatment of a range of diseases. We have developed a synthesis of a novel PI3Kγ inhibitor containing a 1,2-dihydro-3H-pyrrolo[3,4-c]pyridin-3-one scaffold. The key step in the synthesis involved a ruthenium-catalyzed [2 + 2 + 2] cyclotrimerization reaction between a diyne and an alkoxycarbonyl isocyanate, a previously unreported coupling partner in such a reaction.
RESUMO
We have developed versatile methods toward the synthesis of a variety of piperidine/piperazine bridged isosteres of pridopidine. The compounds were assessed against the D2 receptor in agonist and antagonist modes and against the D4 receptor in agonist mode. hERG Binding and the ADME profiles were studied.
Assuntos
Desenho de Fármacos , Piperazina/química , Piperidinas/química , Animais , Compostos Bicíclicos com Pontes/síntese química , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/farmacologia , Cristalografia por Raios X , Antagonistas de Dopamina/síntese química , Antagonistas de Dopamina/química , Antagonistas de Dopamina/farmacologia , Canal de Potássio ERG1/metabolismo , Humanos , Espectroscopia de Ressonância Magnética , Camundongos , Piperazina/síntese química , Piperazina/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D4/agonistas , Receptores de Dopamina D4/antagonistas & inibidores , Relação Estrutura-AtividadeRESUMO
The lipid kinase phosphoinositide 3-kinase γ (PI3Kγ) has attracted attention as a potential target to treat a variety of autoimmune disorders, including multiple sclerosis, due to its role in immune modulation and microglial activation. By minimizing the number of hydrogen bond donors while targeting a previously uncovered selectivity pocket adjacent to the ATP binding site of PI3Kγ, we discovered a series of azaisoindolinones as selective, brain penetrant inhibitors of PI3Kγ. This ultimately led to the discovery of 16, an orally bioavailable compound that showed efficacy in murine experimental autoimmune encephalomyelitis (EAE), a preclinical model of multiple sclerosis.
Assuntos
Encefalomielite Autoimune Experimental/tratamento farmacológico , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Trifosfato de Adenosina/metabolismo , Administração Oral , Animais , Sítios de Ligação , Disponibilidade Biológica , Cristalografia por Raios X , Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/administração & dosagem , Humanos , Ligação de Hidrogênio , Isoenzimas/antagonistas & inibidores , Camundongos Endogâmicos C57BL , Esclerose Múltipla/tratamento farmacológico , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Ftalimidas/química , Relação Estrutura-AtividadeRESUMO
Benzimidazole 1 is the lead compound resulting from an antibacterial program targeting dual inhibitors of bacterial DNA gyrase and topoisomerase IV. With the goal of improving key drug-like properties, namely, the solubility and the formulability of 1, an effort to identify prodrugs was undertaken. This has led to the discovery of a phosphate ester prodrug 2. This prodrug is rapidly cleaved to the parent drug molecule upon both oral and intravenous administration. The prodrug achieved equivalent exposure of 1 compared to dosing the parent in multiple species. The prodrug 2 has improved aqueous solubility, simplifying both intravenous and oral formulation.
RESUMO
A series of high affinity second-generation thiazolopiperidine inhibitors of PI3Kγ were designed based on some general observations around lipid kinase structure. Optimization of the alkylimidazole group led to inhibitors with higher levels of PI3Kγ selectivity. Additional insights into PI3K isoform selectivity related to sequence differences in a known distal hydrophobic pocket are also described.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Piperidinas/química , Piperidinas/farmacologia , Linhagem Celular , Inibidores Enzimáticos/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Isoenzimas/antagonistas & inibidores , Isoenzimas/química , Isoenzimas/metabolismo , Modelos Moleculares , Fosfatidilinositol 3-Quinases/química , Fosfatidilinositol 3-Quinases/metabolismo , Piperidinas/metabolismo , Conformação Proteica , Especificidade por SubstratoRESUMO
Compound 3 is a potent aminobenzimidazole urea with broad-spectrum Gram-positive antibacterial activity resulting from dual inhibition of bacterial gyrase (GyrB) and topoisomerase IV (ParE), and it demonstrates efficacy in rodent models of bacterial infection. Preclinical in vitro and in vivo studies showed that compound 3 covalently labels liver proteins, presumably via formation of a reactive metabolite, and hence presented a potential safety liability. The urea moiety in compound 3 was identified as being potentially responsible for reactive metabolite formation, but its replacement resulted in loss of antibacterial activity and/or oral exposure due to poor physicochemical parameters. To identify second-generation aminobenzimidazole ureas devoid of reactive metabolite formation potential, we implemented a metabolic shift strategy, which focused on shifting metabolism away from the urea moiety by introducing metabolic soft spots elsewhere in the molecule. Aminobenzimidazole urea 34, identified through this strategy, exhibits similar antibacterial activity as that of 3 and did not label liver proteins in vivo, indicating reduced/no potential for reactive metabolite formation.