RESUMO
The P2X4 receptor is a ligand-gated ion channel that is expressed on a variety of cell types, especially those involved in inflammatory and immune processes. High-throughput screening led to a new class of P2X4 inhibitors with substantial CYP 3A4 induction in human hepatocytes. A structure-guided optimization with respect to decreased pregnane X receptor (PXR) binding was started. It was found that the introduction of larger and more polar substituents on the ether linker led to less PXR binding while maintaining the P2X4 inhibitory potency. This translated into significantly reduced CYP 3A4 induction for compounds 71 and 73. Unfortunately, the in vivo pharmacokinetic (PK) profiles of these compounds were insufficient for the desired profile in humans. However, BAY-1797 (10) was identified and characterized as a potent and selective P2X4 antagonist. This compound is suitable for in vivo studies in rodents, and the anti-inflammatory and anti-nociceptive effects of BAY-1797 were demonstrated in a mouse complete Freund's adjuvant (CFA) inflammatory pain model.
Assuntos
Acetamidas/farmacologia , Indutores do Citocromo P-450 CYP3A/farmacologia , Citocromo P-450 CYP3A/metabolismo , Descoberta de Drogas , Inflamação/tratamento farmacológico , Dor/tratamento farmacológico , Antagonistas do Receptor Purinérgico P2X/farmacologia , Receptores Purinérgicos P2X4/química , Acetamidas/química , Animais , Apoptose , Proliferação de Células , Células Cultivadas , Indutores do Citocromo P-450 CYP3A/química , Indução Enzimática , Feminino , Regulação da Expressão Gênica , Humanos , Inflamação/metabolismo , Inflamação/patologia , Ligantes , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Dor/metabolismo , Dor/patologia , Antagonistas do Receptor Purinérgico P2X/química , Ratos , Ratos WistarRESUMO
AZD9272 and AZD6538 are two novel mGluR5 negative allosteric modulators selected for further clinical development. An initial high-throughput screening revealed leads with promising profiles, which were further optimized by minor, yet indispensable, structural modifications to bring forth these drug candidates. Advantageously, both compounds may be synthesized in as little as one step. Both are highly potent and selective for the human as well as the rat mGluR5 where they interact at the same binding site than MPEP. They are orally available, allow for long interval administration due to a high metabolic stability and long half-lives in rats and permeate the blood brain barrier to a high extent. AZD9272 has progressed into phase I clinical studies.