RESUMO
The complement pathway is an important part of the immune system, and uncontrolled activation is implicated in many diseases. The human complement component 5 protein (C5) is a validated drug target within the complement pathway, as an anti-C5 antibody (Soliris) is an approved therapy for paroxysmal nocturnal hemoglobinuria. Here, we report the identification, optimization and mechanism of action for the first small-molecule inhibitor of C5 complement protein.
Assuntos
Complemento C5/antagonistas & inibidores , Bibliotecas de Moléculas Pequenas/farmacologia , Complemento C5/metabolismo , Humanos , Conformação Molecular , Bibliotecas de Moléculas Pequenas/químicaRESUMO
Nicotinamide phosphoribosyltransferase is a key metabolic enzyme that is a potential target for oncology. Utilizing publicly available crystal structures of NAMPT and in silico docking of our internal compound library, a NAMPT inhibitor, 1, obtained from a phenotypic screening effort was replaced with a more synthetically tractable scaffold. This compound then provided an excellent foundation for further optimization using crystallography driven structure based drug design. From this approach, two key motifs were identified, the (S,S) cyclopropyl carboxamide and the (S)-1-N-phenylethylamide that endowed compounds with excellent cell based potency. As exemplified by compound 27e such compounds could be useful tools to explore NAMPT biology in vivo.
Assuntos
Amidas/farmacologia , Ciclopropanos/farmacologia , Citocinas/antagonistas & inibidores , Desenho de Fármacos , Inibidores Enzimáticos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Adenosina/análogos & derivados , Amidas/síntese química , Amidas/química , Cristalografia por Raios X , Ciclopropanos/síntese química , Ciclopropanos/química , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Simulação de Acoplamento Molecular , Estrutura Molecular , Nicotinamida Fosforribosiltransferase/metabolismo , Fenótipo , Relação Estrutura-AtividadeRESUMO
Small molecules that inhibit the metabolic enzyme NAMPT have emerged as potential therapeutics in oncology. As part of our effort in this area, we took a scaffold morphing approach and identified 3-pyridyl azetidine ureas as a potent NAMPT inhibiting motif. We explored the SAR of this series, including 5 and 6 amino pyridines, using a convergent synthetic strategy. This lead optimization campaign yielded multiple compounds with excellent in vitro potency and good ADME properties that culminated in compound 27.
RESUMO
Although cycloadditions of azomethine ylides usually give mixtures of endo/exo adducts, we successfully tuned the mechanistic path of a new reaction cascade to afford substituted pyrrolidines in high yields and diastereomeric purity. This was achieved by forcing the demetalation of tin- or silicon-substituted iminium ions, followed by azomethine ylide cycloaddition and nucleophilic cyclization. Structural complexity is thus built rapidly in a fully controlled one-pot reaction cascade.
Assuntos
Compostos Azo/química , Pirrolidinas/síntese química , Tiossemicarbazonas/química , Ciclização , Estrutura Molecular , Pirrolidinas/química , EstereoisomerismoRESUMO
Although ketone enamines are widely used in organic synthesis, aldehyde enamines are rarely employed due to the limitations of their preparation using known methods (need for acid or base, excess of amine, and/or elevated temperature). We have successfully developed rapid and particularly mild condensation conditions (1 h, 0 degrees C, 1.2 equiv of amine) leading to di- and trisubstituted enamines with excellent conversion (84-100%). Remarkably high chemoselectivity was observed with complete discrimination between aldehyde and ketone, among other functional groups positively tested.