202208-73-9Relevant articles and documents
A Novel Biphenyl-based Chemotype of Retinoid X Receptor Ligands Enables Subtype and Heterodimer Preferences
Pollinger, Julius,Schierle, Simone,Gellrich, Leonie,Ohrndorf, Julia,Kaiser, Astrid,Heitel, Pascal,Chaikuad, Apirat,Knapp, Stefan,Merk, Daniel
supporting information, p. 1346 - 1352 (2019/09/12)
The nuclear retinoid X receptors (RXRs) are key ligand sensing transcription factors that serve as universal nuclear receptor heterodimer partners and are thus involved in numerous physiological processes. Therapeutic targeting of RXRs holds high potential but available RXR activators suffer from limited safety. Selectivity for RXR subtypes or for certain RXR heterodimers are promising strategies for safer RXR modulation. Here, we report systematic structure-activity relationship studies on biphenyl carboxylates as new RXR ligand chemotype. We discovered specific structural modifications that enhance potency on RXRs, govern subtype preference, and vary modulation of different RXR heterodimers. Fusion of these structural motifs enabled specific tuning of subtype preferential profiles with markedly improved potency. Our results provide further evidence that RXR subtype selective ligands can be designed and present a novel chemotype of RXR modulators that can be tuned for subtype and heterodimer preferences.
Identification and initial structure-activity relationships of a novel class of nonpeptide inhibitors of blood coagulation factor Xa
Klein, Scott I.,Czekaj, Mark,Gardner, Charles J.,Guertin, Kevin R.,Cheney, Daniel L.,Spada, Alfred P.,Bolton, Scott A.,Brown, Karen,Colussi, Dennis,Heran, Christopher L.,Morgan, Suzanne R.,Leadley, Robert J.,Dunwiddie, Christopher T.,Perrone, Mark H.,Chu, Valeria
, p. 437 - 450 (2007/10/03)
The discovery and some of the basic structure-activity relationships of a series of novel nonpeptide inhibitors of blood coagulation Factor Xa is described. These inhibitors are functionalized β-alanines, exemplified by 2a. Docking experiments placing 2a in the active site of Factor Xa implied that the most expeditious route to enhancing in vitro potency was to modify the group occupying the S3 site of the enzyme. Increasing the hydrophobic contacts between the inhibitor and the enzyme in this region led to 8, which has served as the prototype for this series. In addition, an enantioselective synthesis of these substituted β-alanines was also developed.
