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1.
Bioorg Med Chem Lett ; 19(19): 5807-10, 2009 Oct 01.
Article in English | MEDLINE | ID: mdl-19713106

ABSTRACT

The SAR of a series of 1-amino-3-(1H-indol-1-yl)-3-phenylpropan-2-ols as monoamine reuptake inhibitors, with a goal to improve both potency toward inhibiting the norepinephrine transporter and selectivity over the serotonin transporter, is reported. The effect of specific substitution on both the 3-phenyl group and the indole moiety were explored. This study led to the discovery of compound 20 which inhibited the norepinephrine transporter with an IC50 value of 4 nM while exhibiting 86-fold selectivity over the serotonin transporter.


Subject(s)
Adrenergic Uptake Inhibitors/chemistry , Indoles/chemistry , Norepinephrine Plasma Membrane Transport Proteins/antagonists & inhibitors , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/pharmacokinetics , Animals , Humans , Indoles/chemical synthesis , Indoles/pharmacokinetics , Models, Animal , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Rats , Serotonin Plasma Membrane Transport Proteins/chemistry , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacokinetics , Stereoisomerism , Structure-Activity Relationship
2.
J Med Chem ; 52(7): 2148-52, 2009 Apr 09.
Article in English | MEDLINE | ID: mdl-19271735

ABSTRACT

A potent, highly insoluble, GnRH antagonist with a 2-phenyl-4-piperazinylbenzimidazole template and a quinoxaline-2,3-dione pharmacophore was modified to maintain GnRH antagonist activity and improve in vitro pharmaceutical properties. Structural changes to the quinoxaline-2,3-dione portion of the molecule resulted in several structures with improved properties and culminated in the discovery of 6-([4-[2-(4-tert-butylphenyl)-1H-benzimidazol-4-yl]piperazin-1-yl] methyl)quinoxaline (WAY-207024). The compound was shown to have excellent pharmacokinetic parameters and lowered rat plasma LH levels after oral administration.


Subject(s)
Benzimidazoles/chemical synthesis , Quinoxalines/chemical synthesis , Receptors, LHRH/antagonists & inhibitors , Administration, Oral , Animals , Benzimidazoles/chemistry , Benzimidazoles/pharmacology , Binding, Competitive , Biological Availability , Half-Life , Humans , In Vitro Techniques , Luteinizing Hormone/blood , Male , Microsomes, Liver/metabolism , Orchiectomy , Pituitary Gland/drug effects , Pituitary Gland/metabolism , Quinoxalines/chemistry , Quinoxalines/pharmacology , Radioligand Assay , Rats , Structure-Activity Relationship
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