RESUMO
A valid PLS-DA model to predict attrition in pre-clinical toxicology for basic oral candidate drugs was built. A combination of aromatic/aliphatic balance, flatness, charge distribution and size descriptors helped predict the successful progression of compounds through a wide range of toxicity testing. Eighty percent of an independent test set of marketed post-2000 basic drugs could be successfully classified using the model, indicating useful forward predictivity. The themes within this work provide additional guidance for medicinal design chemists and complement other literature property guidelines.
Assuntos
Desenho de Fármacos , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica/métodos , Modelos Estatísticos , Testes de Toxicidade/métodos , Animais , Análise Discriminante , Humanos , Estrutura Molecular , Preparações Farmacêuticas/química , Preparações Farmacêuticas/metabolismoAssuntos
Descoberta de Drogas , Antagonistas do Receptor Purinérgico P2 , Amidas/química , Amidas/farmacologia , Amidas/uso terapêutico , Amidinas/química , Amidinas/farmacologia , Amidinas/uso terapêutico , Animais , Artrite Reumatoide/tratamento farmacológico , Azóis/química , Azóis/farmacologia , Azóis/uso terapêutico , Humanos , Receptores Purinérgicos P2X7 , Relação Estrutura-AtividadeRESUMO
Starting from adenosine triphosphate (ATP), the identification of a novel series of P2Y(12) receptor antagonists and exploitation of their SAR is described. Modifications of the acidic side chain and the purine core and investigation of hydrophobic substituents led to a series of neutral molecules. The leading compound, 17 (AZD6140), is currently in a large phase III clinical trial for the treatment of acute coronary syndromes and prevention of thromboembolic clinical sequelae.
Assuntos
Trifosfato de Adenosina/uso terapêutico , Adenosina/análogos & derivados , Proteínas de Membrana/antagonistas & inibidores , Antagonistas do Receptor Purinérgico P2 , Trombose/prevenção & controle , Adenosina/uso terapêutico , Administração Oral , Animais , Humanos , Receptores Purinérgicos P2Y12 , TicagrelorRESUMO
We have previously described a novel series of potent blockers of the monocarboxylate transporter, MCT1, which show potent immunomodulatory activity in an assay measuring inhibition of PMA/ionomycin-induced human PBMC proliferation. However, the preferred compounds had the undesirable property of existing as a mixture of slowly interconverting rotational isomers. Here we show that variable temperature NMR is an effective method of monitoring how alteration to the nature of the amide substituent can modulate the rate of isomer exchange. This led to the design of compounds with increased rates of rotamer interconversion. Moreover, some of these compounds also showed improved potency and provided a route to further optimization.
