92501-88-7Relevant academic research and scientific papers
Oxime Carbamate-Discovery of a series of novel FAAH inhibitors
Sit,Conway, Charles M.,Xie, Kai,Bertekap, Robert,Bourin, Clotilde,Burris, Kevin D.
supporting information; experimental part, p. 1272 - 1277 (2010/06/17)
A series of novel oxime carbamates have been identified as potent inhibitors of the key regulatory enzyme of the endocannabinoid signaling system, fatty acid amide hydrolase (FAAH). In this Letter, the rationale behind the discovery and the biological evaluations of this novel class of FAAH inhibitors are presented. Both in vitro and in vivo results of selected targets are discussed, along with inhibition kinetics and molecular modeling studies.1.
1,2,3,6-TETRAHYDROAZEPINO[4,5-B]INDOLE-5-CARBOXYLATE NUCLEAR RECEPTOR INHIBITORS
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Page/Page column 57-58, (2010/04/27)
Provided are certain 1,2,3,6- tetrahydroazepino[4,5-b]indole-5-carboxylate compounds which are useful for modulating the activity of nuclear receptors, such as farnesoid X receptors, and/or for the treatment, prevention, or amelioration diseases or disorders related to the activity of these receptors.
Improvement of physiochemical properties of the tetrahydroazepinoindole series of farnesoid X receptor (FXR) agonists: Beneficial modulation of lipids in primates
Lundquist IV, Joseph T.,Harnish, Douglas C.,Kim, Callain Y.,Mehlmann, John F.,Unwalla, Rayomand J.,Phipps, Kristin M.,Crawley, Matthew L.,Commons, Thomas,Green, Daniel M.,Xu, Weixin,Hum, Wah-Tung,Eta, Julius E.,Feingold, Irene,Patel, Vikram,Evans, Mark J.,Lai, Kehdih,Borges-Marcucci, Lisa,Mahaney, Paige E.,Wrobel, Jay E.
experimental part, p. 1774 - 1787 (2010/08/06)
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 dosedependent 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.
