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2.
J Med Chem ; 50(4): 807-19, 2007 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-17249648

RESUMO

The discovery of a novel series of NR2B subtype selective N-methyl-d-aspartate (NMDA) antagonists is reported. Initial optimization of a high-throughput screening lead afforded an aminopyridine derivative 13 with significant NR2B antagonist potency but limited selectivity over hERG-channel and other off-target activities. Further structure-activity studies on the aminoheterocycle moiety and optimization of the carbamate led to the highly potent 2-aminopyrimidine derivative 20j with a significantly improved off-target activity profile and oral bioavailability in multiple species coupled with good brain penetration. Compound 20j demonstrated efficacy in in vivo rodent models of antinociception, allodynia, and Parkinson's disease.


Assuntos
Analgésicos/síntese química , Encéfalo/metabolismo , Pirimidinas/síntese química , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Administração Oral , Analgésicos/farmacocinética , Analgésicos/farmacologia , Animais , Antiparkinsonianos/síntese química , Antiparkinsonianos/farmacocinética , Antiparkinsonianos/farmacologia , Disponibilidade Biológica , Linhagem Celular , Cães , Feminino , Lobo Frontal/metabolismo , Humanos , Masculino , Medição da Dor , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Relação Estrutura-Atividade
4.
J Org Chem ; 61(14): 4725-4738, 1996 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-11667404

RESUMO

An investigation of the scope and mechanism of a new synthesis of cyclopentenes from 3,6-dihydro-2H-thiopyrans is described. Alkyl halides substituted with an electron-withdrawing group in the alpha-position were reacted with sodium thiosulfate, yielding the corresponding Bunte salts, which could be transformed to reactive thiocarbonyl compounds by elimination of the elements of bisulfite with mild base treatment. In situ trapping by 1,3-dienes afforded in good yields a variety of 3,6-dihydro-2H-thiopyrans substituted with electron-withdrawing groups at the 2-position. Exposure of these cycloadducts to strong base at low temperature effected a novel ring contraction, affording 2-(methylthio)-3-cyclopentenes after quenching with methyl iodide. The level of diastereoselectivity exhibited during the generation of these cyclopentenes was found to be dependent on the nature of the electron-withdrawing group at the 2-position of the dihydrothiopyran as well as the substitution pattern originally present in the diene component. In some cases, reducing the temperature during the ring contraction resulted in the isolation of good yields of vinyl cyclopropanes of high isomeric purity. With one substrate, highly diastereoselective rearrangement of a vinyl cyclopropane to a cyclopentene was unambiguously demonstrated, suggesting that this might be a key feature of the overall ring contraction mechanism.

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