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1.
J Med Chem ; 48(10): 3478-80, 2005 May 19.
Article in English | MEDLINE | ID: mdl-15887956

ABSTRACT

A series of 5-(piperidinylethyloxy)quinoline 5-hydroxytryptamine(1D) (5-HT(1D)) receptor antagonists have been discovered from elaboration of the series of dual 5-hydroxytryptamine(1)-selective serotonin reuptake inhibitors (5HT(1)-SSRIs) reported previously. This is the first report of highly potent, selective antagonists for the 5-HT(1D) receptor, which represents an extremely useful set of pharmacological tools for further understanding the roles of the 5-HT(1) receptor subtypes.


Subject(s)
Piperazines/chemical synthesis , Quinolines/chemical synthesis , Serotonin 5-HT1 Receptor Antagonists , Animals , Binding, Competitive , CHO Cells , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Cricetinae , Cricetulus , In Vitro Techniques , Piperazines/chemistry , Piperazines/pharmacology , Quinolines/chemistry , Quinolines/pharmacology , Radioligand Assay , Rats , Serotonin 5-HT1 Receptor Agonists , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity Relationship
2.
Bioorg Med Chem Lett ; 13(10): 1627-9, 2003 May 19.
Article in English | MEDLINE | ID: mdl-12729628

ABSTRACT

Starting from a series of 7-linked tetrahydroisoquinoline derivatives, as exemplified by SB-270664, a new series of 8,8-dimethylnaphthyridine compounds has been identified. SAR studies around these attractive leads have provided compounds such as 12 which display excellent anticonvulsant activity and an encouraging pharmacokinetic profile in vivo.


Subject(s)
Anticonvulsants/chemical synthesis , Naphthyridines/chemical synthesis , Naphthyridines/pharmacokinetics , Administration, Oral , Animals , Anticonvulsants/pharmacokinetics , Anticonvulsants/pharmacology , Dose-Response Relationship, Drug , Drug Design , Naphthyridines/pharmacology , Rats , Seizures/drug therapy , Seizures/prevention & control , Structure-Activity Relationship , Tetrahydroisoquinolines
3.
J Med Chem ; 45(5): 999-1001, 2002 Feb 28.
Article in English | MEDLINE | ID: mdl-11855979

ABSTRACT

Screening of our internal compound collection for inhibitors of the transforming growth factor beta1 (TGF-beta1) type I receptor (ALK5) identified several hits. Optimization of the dihydropyrroloimidazole hit 2 by introduction of a 2-pyridine and 3,4-methylenedioxyphenyl group gave 7, a selective ALK5 inhibitor. With this information, optimization of the triarylimidazole hit 8 gave the selective inhibitor 14, which inhibits TGF-beta1-induced fibronectin mRNA formation while displaying no measurable cytotoxicity in the 48 h XTT assay.


Subject(s)
Activin Receptors, Type I/antagonists & inhibitors , Enzyme Inhibitors/chemical synthesis , Imidazoles/chemical synthesis , Receptors, Transforming Growth Factor beta/antagonists & inhibitors , DNA-Binding Proteins/metabolism , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fibronectins/biosynthesis , Fibronectins/genetics , Humans , Imidazoles/chemistry , Imidazoles/pharmacology , Mitogen-Activated Protein Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases , RNA, Messenger/biosynthesis , Receptor, Transforming Growth Factor-beta Type I , Smad3 Protein , Structure-Activity Relationship , Trans-Activators/metabolism , Tumor Cells, Cultured , p38 Mitogen-Activated Protein Kinases
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