Discovery and structure-activity relationships of a series of pyroglutamic acid amide antagonists of the P2X7 receptor.

Abdi, Muna H; Beswick, Paul J; Billinton, Andy; Chambers, Laura J; Charlton, Andrew; Collins, Sue D; Collis, Katharine L; Dean, David K; Fonfria, Elena; Gleave, Robert J; Lejeune, Clarisse L; Livermore, David G; Medhurst, Stephen J; Michel, Anton D; Moses, Andrew P; Page, Lee; Patel, Sadhana; Roman, Shilina A; Senger, Stefan; Slingsby, Brian; Steadman, Jon G A; Stevens, Alexander J; Walter, Daryl S

Abdi, Muna H; Beswick, Paul J; Billinton, Andy; Chambers, Laura J; Charlton, Andrew; Collins, Sue D; Collis, Katharine L; Dean, David K; Fonfria, Elena; Gleave, Robert J; Lejeune, Clarisse L; Livermore, David G; Medhurst, Stephen J; Michel, Anton D; Moses, Andrew P; Page, Lee; Patel, Sadhana; Roman, Shilina A; Senger, Stefan; Slingsby, Brian; Steadman, Jon G A; Stevens, Alexander J; Walter, Daryl S.

Afiliação

Abdi MH; Neurosciences Centre of Excellence for Drug Discovery, GlaxoSmithKline, New Frontiers Science Park, Harlow, Essex, UK.

Bioorg Med Chem Lett ; 20(17): 5080-4, 2010 Sep 01.

Article em En | MEDLINE | ID: mdl-20673717

RESUMO

A computational lead-hopping exercise identified compound 4 as a structurally distinct P2X(7) receptor antagonist. Structure-activity relationships (SAR) of a series of pyroglutamic acid amide analogues of 4 were investigated and compound 31 was identified as a potent P2X(7) antagonist with excellent in vivo activity in animal models of pain, and a profile suitable for progression to clinical studies.

Assuntos

Amidas/farmacologia; Antagonistas do Receptor Purinérgico P2/farmacologia; Ácido Pirrolidonocarboxílico/química; Receptores Purinérgicos P2X7/efeitos dos fármacos; Amidas/química; Descoberta de Drogas; Modelos Moleculares; Antagonistas do Receptor Purinérgico P2/química; Relação Estrutura-Atividade

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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Ácido Pirrolidonocarboxílico / Receptores Purinérgicos P2X7 / Antagonistas do Receptor Purinérgico P2 / Amidas Idioma: En Revista: Bioorg Med Chem Lett Assunto da revista: BIOQUIMICA / QUIMICA Ano de publicação: 2010 Tipo de documento: Article País de publicação: Reino Unido

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