Pyridyl-phenyl ether monoamine reuptake inhibitors: Impact of lipophilicity on dual SNRI pharmacology and off-target promiscuity.

Whitlock, Gavin A; Fish, Paul V; Fray, M Jonathan; Stobie, Alan; Wakenhut, Florian

Whitlock, Gavin A; Fish, Paul V; Fray, M Jonathan; Stobie, Alan; Wakenhut, Florian.

Afiliação

Whitlock GA; Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK. gavin.whitlock@pfizer.com

Bioorg Med Chem Lett ; 18(9): 2896-9, 2008 May 01.

Article em En | MEDLINE | ID: mdl-18417343

ABSTRACT

ABSTRACT

A novel series of pyridyl-phenyl ethers are disclosed, which possess dual 5-HT and NA reuptake pharmacology with good selectivity over dopamine reuptake inhibition. An analysis of the relationship between lipophilicity and pharmacology highlighted that potent dual SNRI activity was only achievable at c log P>3.5. The series was found to possess significant polypharmacology issues, and we concluded that this off-target promiscuity was related to lipophilicity.

Assuntos

Aminas/farmacologia; Hepatócitos/efeitos dos fármacos; Norepinefrina/antagonistas & inibidores; Éteres Fenílicos/farmacologia; Piridinas/farmacologia; Inibidores Seletivos de Recaptação de Serotonina/farmacologia; Antagonistas do Receptor 5-HT1 de Serotonina; Aminas/síntese química; Hepatócitos/metabolismo; Humanos; Concentração Inibidora 50; Modelos Químicos; Éteres Fenílicos/síntese química; Piridinas/síntese química; Inibidores Seletivos de Recaptação de Serotonina/síntese química; Relação Estrutura-Atividade

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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Éteres Fenílicos / Piridinas / Norepinefrina / Inibidores Seletivos de Recaptação de Serotonina / Hepatócitos / Antagonistas do Receptor 5-HT1 de Serotonina / Aminas Limite: Humans Idioma: En Ano de publicação: 2008 Tipo de documento: Article

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