RESUMO
Herein we describe a series of tetrahydrobenzotriazoles as novel, potent metabotropic glutamate receptor subtype 5 (mGlu5) positive allosteric modulators (PAMs). Exploration of the SAR surrounding the tetrahydrobenzotriazole core ultimately led to the identification of 29 as a potent mGlu5 PAM with a low maximal glutamate potency fold shift, acceptable in vitro DMPK parameters and in vivo PK profile and efficacy in the rat novel object recognition (NOR) assay. As a result 29 was identified as a suitable compound for progression to in vivo safety evaluation.
Assuntos
Antipsicóticos/química , Receptor de Glutamato Metabotrópico 5/antagonistas & inibidores , Triazóis/química , Regulação Alostérica/efeitos dos fármacos , Animais , Antipsicóticos/metabolismo , Antipsicóticos/farmacologia , Astrócitos/citologia , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Cognição/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Meia-Vida , Humanos , Microssomos/metabolismo , Ratos , Receptor de Glutamato Metabotrópico 5/metabolismo , Relação Estrutura-Atividade , Triazóis/metabolismo , Triazóis/farmacologiaRESUMO
A flow-based route to imatinib, the API of Gleevec, was developed and the general procedure then used to generate a number of analogues which were screened for biological activity against Abl1. The flow synthesis required minimal manual intervention and was achieved despite the poor solubility of many of the reaction components.
Assuntos
Benzamidas/síntese química , Técnicas de Química Combinatória/métodos , Piperazinas/síntese química , Pirimidinas/síntese química , Benzamidas/química , Técnicas de Química Combinatória/instrumentação , Mesilato de Imatinib , Estrutura Molecular , Piperazinas/química , Pirimidinas/químicaRESUMO
Imatinib (1), nilotinib (2) and dasatinib (3) are Bcr-Abl tyrosine kinase inhibitors approved for the treatment of chronic myelogenous leukemia (CML). This review collates information from the journal and patent literature to provide a comprehensive reference source of the different synthetic methods used to prepare the aforementioned active pharmaceutical ingredients (API's).
Assuntos
Antineoplásicos/síntese química , Antineoplásicos/farmacologia , Benzamidas/síntese química , Proteínas de Fusão bcr-abl/antagonistas & inibidores , Piperazinas/síntese química , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/síntese química , Tiazóis/síntese química , Antineoplásicos/química , Benzamidas/química , Benzamidas/farmacologia , Dasatinibe , Proteínas de Fusão bcr-abl/metabolismo , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Leucemia Mielogênica Crônica BCR-ABL Positiva/enzimologia , Piperazinas/química , Piperazinas/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Pirimidinas/química , Pirimidinas/farmacologia , Relação Estrutura-Atividade , Tiazóis/química , Tiazóis/farmacologiaRESUMO
A concise, flow-based synthesis of Imatinib, a compound used for the treatment of chronic myeloid leukaemia, is described whereby all steps are conducted in tubular flow coils or cartridges packed with reagents or scavengers to effect clean product formation. An in-line solvent switching procedure was developed enabling the procedure to be performed with limited manual handling of intermediates.
Assuntos
Antineoplásicos/síntese química , Piperazinas/síntese química , Pirimidinas/síntese química , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Benzamidas , Dimetilaminas/química , Humanos , Mesilato de Imatinib , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Piperazina , Piperazinas/química , Piperazinas/uso terapêutico , Pirimidinas/química , Pirimidinas/uso terapêuticoRESUMO
A fully automated flow-through process for the production of secondary sulfonamides is presented. Primary sulfonamides were monoalkylated using a two-step "catch and release" protocol to generate library products of high purity. The automated flow synthesis platform incorporates four independent reactor columns and is able to perform automated column regeneration. A 48-member sulfonamide library was prepared as two 24-member sublibraries, affording library compounds in good yields and high purities without the need for further column chromatographic purification.