RESUMO
A large body of compelling preclinical evidence supports the clinical use of neurokinin (NK) receptor antagonists in a plethora of CNS and non-CNS therapeutic areas. The significant investment made in this area over the past 2 decades culminated with the observation that NK(1) receptor antagonists elicited clinical efficacy in major depression disorders. In addition, aprepitant (Merck) was launched as a new drug able to prevent chemotherapy-induced nausea and vomiting (CINV). After the discovery by GlaxoSmithKline of vestipitant, a wide drug discovery program was launched aimed at identifying additional clinical candidates. New compounds were designed to maximize affinity at the NK(1) receptor binding site while retaining suitable physicochemical characteristics to ensure excellent pharmacokinetic and pharmacodynamic properties in vivo. Herein we describe the discovery process of a new NK(1) receptor antagonist (casopitant) selected as clinical candidate and progressed into clinical studies to treat major depression disorders.
Assuntos
Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Transtorno Depressivo/tratamento farmacológico , Antagonistas dos Receptores de Neurocinina-1 , Piperazinas/síntese química , Piperazinas/farmacologia , Piperidinas/síntese química , Piperidinas/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Células CHO , Cricetinae , Cricetulus , Transtorno Depressivo/metabolismo , Descoberta de Drogas , Gerbillinae , Meia-Vida , Humanos , Espectroscopia de Ressonância Magnética , Piperazinas/química , Piperazinas/farmacocinética , Piperidinas/química , Piperidinas/farmacocinética , Análise de Regressão , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Infravermelho , EstereoisomerismoRESUMO
Liquid chromatography-NMR (LC-NMR) spectroscopy was used to obtain detailed information regarding the structure of the major bulk drug impurities present in GW597599 (vestipitant). The one-dimensional (1)H LC-NMR experiments were performed in both continuous and stop-flow modes on a sample of GW597599 (vestipitant) enriched with mother liquor impurities. The information derived from both LC-NMR and LC-MS data provided the structural information of all major impurities. The full characterisation of the impurities by high-resolution NMR spectroscopy was ultimately performed on appropriately synthesised compounds.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Contaminação de Medicamentos , Indústria Farmacêutica/métodos , Espectroscopia de Ressonância Magnética/métodos , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/análise , Fluorbenzenos , Espectrometria de Massas/métodos , Estrutura Molecular , Piperidinas/síntese química , Piperidinas/química , SoluçõesRESUMO
Vestipitant (1) is a novel NK1 antagonist currently under investigation for the treatment of CNS disorders and emesis. The first synthetic step comprised a Grignard synthesis. An impurity was identified and initially expected to be a symmetric biphenyl. This paper reports the work to synthesise the supposed structure and the spectroscopic analyses (LC-NMR and HR-NMR) to correctly identify the real structure and understand the chemical pathway of the impurity.
Assuntos
Compostos de Bifenilo/química , Contaminação de Medicamentos , Espectroscopia de Ressonância Magnética/métodos , Antagonistas dos Receptores de Neurocinina-1 , Piperidinas/química , Cromatografia Líquida de Alta Pressão , Fluorbenzenos , Piperidinas/síntese químicaRESUMO
In an effort to discover novel druglike NK(1) receptor antagonists a new series of suitably substituted C-phenylpiperazine derivatives was identified by an appropriate chemical exploration of related N-phenylpiperazine analogues, with the specific aim to maximize their in vitro affinity and optimize in parallel their pharmacokinetic profile. Among the compounds synthesized, 2-(S)-(4-fluoro-2-methylphenyl)piperazine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethylphenyl)ethyl]methylamide (vestipitant) was identified as one of the most in vitro potent and selective NK(1) receptor antagonists ever discovered, showing appropriate pharmacokinetic properties and in vivo activity. On the basis of its preclinical profile, this compound was selected as a drug candidate.