186552-02-3Relevant academic research and scientific papers
3,4,5-Trisubstituted isoxazoles as novel PPARδ agonists. Part 2
Epple, Robert,Azimioara, Mihai,Russo, Ross,Xie, Yongping,Wang, Xing,Cow, Christopher,Wityak, John,Karanewsky, Don,Bursulaya, Badry,Kreusch, Andreas,Tuntland, Tove,Gerken, Andrea,Iskandar, Maya,Saez, Enrique,Martin Seidel,Tian, Shin-Shay
, p. 5488 - 5492 (2007/10/03)
A series of PPARδ-selective agonists was investigated and optimized for a favorable in vivo pharmacokinetic profile. Isoxazole LCI765 (17d) was found to be a potent and selective PPARδ agonist with good in vivo PK properties in mouse (Cmax = 5.1 μM, t1/2 = 3.1 h). LCI765 regulated expression of genes involved in energy homeostasis in relevant tissues when dosed orally in C57BL6 mice. A co-crystal structure of compound LCI765 and the LBD of PPARδ is discussed.
Sulfonamidopyrrolidinone factor Xa inhibitors: Potency and selectivity enhancements via P-1 and P-4 optimization
Choi-Sledeski, Yong Mi,McGarry, Daniel G.,Green, Daniel M.,Mason, Helen J.,Becker, Michael R.,Davis, Roderick S.,Ewing, William R.,Dankulich, William P.,Manetta, Vincent E.,Morris, Robert L.,Spada, Alfred P.,Cheney, Daniel L.,Brown, Karen D.,Colussi, Dennis J.,Valeria, Chu,Heran, Christopher L.,Morgan, Suzanne R.,Bentley, Ross G.,Leadley, Robert J.,Maignan, Sebastien,Guilloteau, Jean-Pierre,Dunwiddie, Christopher T.,Pauls, Henry W.
, p. 3572 - 3587 (2007/10/03)
Sulfonamidopyrrolidinones were previously disclosed as a selective class of factor Xa (fXa) inhibitors, culminating in the identification of RPR120844 as a potent member with efficacy in vivo. Recognizing the usefulness of the central pyrrolidinone template for the presentation of ligands to the S-1 and S-4 subsites of fXa, studies to optimize the P-1 and P-4 groups were initiated. Sulfonamidopyrrolidinones containing 4-hydroxy- and 4- aminobenzamidines were discovered to be effective inhibitors of fXa. X-ray crystallographic experiments in trypsin and molecular modeling studies suggest that our inhibitors bind by insertion of the 4-hydroxybenzamidine moiety into the S-1 subsite of the fXa active site. Of the P-4 groups examined, the pyridylthienyl sulfonamides were found to confer excellent potency and selectivity especially in combination with 4-hydroxybenzamidine. Compound 20b (RPR130737) was shown to be a potent fXa inhibitor (K1 = 2 nM) with selectivity against structurally related serine proteinases (> 1000 times). Preliminary biological evaluation demonstrates the effectiveness of this inhibitor in common assays of thrombosis in vitro (e.g. activated partial thromboplastin time) and in vivo (e.g. rat FeCl2-induced carotid artery thrombosis model).
