RESUMO
Tackling PPIs, particularly by stabilizing clinically favored conformations of target proteins, with orally available, bona fide small molecules remains a significant but immensely worthwhile challenge for the pharmaceutical industry. Success may be more likely through the application of nature's learnings to build intrinsic rigidity into the design of clinical candidates.
Assuntos
Desenho de Fármacos , Domínios e Motivos de Interação entre Proteínas/efeitos dos fármacos , Estabilidade Proteica/efeitos dos fármacos , Proteínas/metabolismo , Bibliotecas de Moléculas Pequenas/farmacologia , Descoberta de Drogas , Humanos , Ligação Proteica , Bibliotecas de Moléculas Pequenas/químicaRESUMO
For over 30 years, rapamycin has generated a sustained and intense interest from the scientific community as a result of its exceptional pharmacological properties and challenging structural features. In addition to its well known therapeutic value as a potent immunosuppressive agent, rapamycin and its derivatives have recently gained prominence for the treatment of a wide variety of other human malignancies. Herein we disclose full details of our extensive investigation into the synthesis of rapamycin that culminated in a new and convergent preparation featuring a macro-etherification/catechol-templating strategy for construction of the macrocyclic core of this natural product.
Assuntos
Antineoplásicos/síntese química , Produtos Biológicos/síntese química , Imunossupressores/síntese química , Sirolimo/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Ciclização , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Estrutura Molecular , Sirolimo/química , Sirolimo/farmacologiaRESUMO
The novel 7-transmembrane receptor MrgX1 is located predominantly in the dorsal root ganglion and has consequently been implicated in the perception of pain. Here we describe the discovery and optimization of a small molecule agonist and initial docking studies of this ligand into the receptor in order to provide a suitable lead and tool compound for the elucidation of the physiological function of the receptor.
Assuntos
Piperazinas/síntese química , Piridazinas/síntese química , Receptores Acoplados a Proteínas G/agonistas , Compostos de Bifenilo/síntese química , Compostos de Bifenilo/farmacologia , Cálcio/metabolismo , Técnicas de Química Combinatória , Desenho de Fármacos , Humanos , Piperazinas/farmacologia , Piridazinas/farmacologia , Receptores Acoplados a Proteínas G/fisiologia , Relação Estrutura-AtividadeRESUMO
A novel oxytocin antagonist was identified by 'scaffold-hopping' using Cresset FieldScreen molecular field similarity searching. A single cycle of optimization driven by an understanding of the key pharmacophoric elements required for activity led to the discovery of a potent, selective and highly ligand-efficient oxytocin receptor antagonist. Selectivity over vasopressin receptors was rationalized based on differences in the structure of the natural ligands.
Assuntos
Desenho de Fármacos , Ocitocina/química , Receptores de Ocitocina/antagonistas & inibidores , Receptores de Vasopressinas/química , Vasopressinas/química , Química Farmacêutica/métodos , Feminino , Humanos , Cinética , Ligantes , Modelos Químicos , Conformação Molecular , Trabalho de Parto Prematuro/tratamento farmacológico , Gravidez , Vasotocina/análogos & derivados , Vasotocina/químicaRESUMO
The optimisation of a tertiary sulfonamide high-throughput screening hit is described. A combination of high-throughput chemistry, pharmacophore analysis and in silico PK profiling resulted in the discovery of potent sulfonamide oxytocin receptor antagonists with oral exposure and good selectivity over vasopressin receptors.