Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 2 de 2
Filter
Add more filters










Database
Language
Publication year range
1.
J Med Chem ; 53(4): 1774-87, 2010 Feb 25.
Article in English | MEDLINE | ID: mdl-20095622

ABSTRACT

In an effort to develop orally active farnesoid X receptor (FXR) agonists, a series of tetrahydroazepinoindoles with appended solubilizing amine functionalities were synthesized. The crystal structure of the previously disclosed FXR agonist, 1 (FXR-450), aided in the design of compounds with tethered solubilizing functionalities designed to reach the solvent cavity around the hFXR receptor. These compounds were soluble in 0.5% methylcellulose/2% Tween-80 in water (MC/T) for oral administration. In vitro and in vivo optimization led to the identification of 14dd and 14cc, which in a dose-dependent fashion regulated low density lipoprotein cholesterol (LDLc) in low density lipoprotein receptor knockout (LDLR(-/-)) mice. Compound 14cc was dosed in female rhesus monkeys for 4 weeks at 60 mg/kg daily in MC/T vehicle. After 7 days, triglyceride (TG) levels and very low density lipoprotein cholesterol (VLDLc) levels were significantly decreased and LDLc was decreased 63%. These data are the first to demonstrate the dramatic lowering of serum LDLc levels by a FXR agonist in primates and supports the potential utility of 14cc in treating dyslipidemia in humans beyond just TG lowering.


Subject(s)
Azepines/chemical synthesis , Hypolipidemic Agents/chemical synthesis , Indoles/chemical synthesis , Receptors, Cytoplasmic and Nuclear/agonists , Animals , Azepines/pharmacokinetics , Azepines/pharmacology , Biological Availability , Cell Line , Cholesterol, LDL/blood , Female , Humans , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Indoles/pharmacokinetics , Indoles/pharmacology , Macaca mulatta , Male , Mice , Mice, Knockout , Microsomes, Liver/metabolism , Models, Molecular , Rats , Rats, Sprague-Dawley , Receptors, LDL/genetics , Solubility , Structure-Activity Relationship , Triglycerides/blood
2.
Org Lett ; 11(5): 1183-5, 2009 Mar 05.
Article in English | MEDLINE | ID: mdl-19209924

ABSTRACT

An efficient and mild method to couple aryl bromides and activated non-allylic alcohols in a Heck reaction with tandem isomerization to selectively afford high yields of 1,5-diarylalkan-1-ones has been developed. Mechanistic insight was gained through NMR studies of products derived from deuterium-labeled intermediates.


Subject(s)
Benzyl Alcohols/chemistry , Bromides/chemistry , Palladium/chemistry , Catalysis , Magnetic Resonance Spectroscopy , Molecular Structure , Stereoisomerism
SELECTION OF CITATIONS
SEARCH DETAIL
...