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1.
J Med Chem ; 53(8): 3296-304, 2010 Apr 22.
Article in English | MEDLINE | ID: mdl-20350005

ABSTRACT

A series of phenyl sulfone substituted quinoxaline were prepared and the lead compound 13 (WYE-672) was shown to be a tissue selective LXR Agonist. Compound 13 demonstrated partial agonism for LXRbeta in kidney HEK-293 cells but did not activate Gal4 LXRbeta fusion proteins in huh-7 liver cells. Although 13 showed potent binding affinity to LXRbeta (IC(50) = 53 nM), it had little binding affinity for LXRalpha (IC(50) > 1.0 microM) and did not recruit any coactivator/corepressor peptides in the LXRalpha multiplex assay. However, compound 13 showed good agonism in THP-1 cells with respect to increasing ABCA1 gene expression and good potency on cholesterol efflux in THP-1 foam cells. In an eight-week lesion study in LDLR -/- mice, compound 13 showed reduction of aortic arch lesion progression and no plasma or hepatic triglyceride increase. These results suggest quinoxaline 13 may have an improved biological profile for potential use as a therapeutic agent.


Subject(s)
Orphan Nuclear Receptors/agonists , Quinoxalines/chemical synthesis , Sulfones/chemical synthesis , ATP Binding Cassette Transporter 1 , ATP-Binding Cassette Transporters/biosynthesis , Animals , Area Under Curve , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Cell Line , Cholesterol/metabolism , Duodenum/metabolism , Half-Life , Humans , Kidney/metabolism , Liver/metabolism , Liver X Receptors , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Models, Molecular , Organ Specificity , Orphan Nuclear Receptors/genetics , Quinoxalines/chemistry , Quinoxalines/pharmacology , Radioligand Assay , Structure-Activity Relationship , Sulfones/chemistry , Sulfones/pharmacology , Transcriptional Activation , Triglycerides/metabolism
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
3.
Bioorg Med Chem Lett ; 15(15): 3514-8, 2005 Aug 01.
Article in English | MEDLINE | ID: mdl-15982877

ABSTRACT

We synthesized and evaluated a novel series of 2-carboxylic acid indole-based inhibitors of plasminogen activator inhibitor-1 (PAI-1). Systematic modification of the N-1 position and the 5-position of the indole scaffold resulted in the identification of several compounds that showed good potency against PAI-1 in the spectrophotometric assay. This potency did not always translate to the antibody assay. Solubility and serum protein binding studies on selected analogs revealed that protein binding might be a factor in the poor correlation between the two assays.


Subject(s)
Indoles/chemical synthesis , Indoles/pharmacology , Plasminogen Activator Inhibitor 1/metabolism , Binding Sites , Carboxylic Acids , Enzyme-Linked Immunosorbent Assay , Spectrophotometry , Structure-Activity Relationship
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