AR ligands

SARMs are AR ligands that display tissue-specific androgenic/antiandrogenic activities. 

The bicyclic system of isoquinoline and quinazoline has been replaced by several monocyclic rings (Van Muijlwijk-Koezen et al. 2001). Some thiazole and thiadiazole derivatives revealed to be the most promising candidates for the identification of new A3 AR ligands. 

Some 2 and 3 -fluoro analogues of Cl-IB-MECA have been investigated as A3 AR ligands (Lim et al. 2003). While the introduction of a fluorine atom at the 2 -position compromised both A3 AR binding and activation, the 3 -fluoro substitution generally resulted in partial agonism. Compound 27 is one of the few ligands... 

CO)(02(PPh3)2(Ar)] wherein Ar = Ph, w-MeC6H4 and p-MeC6H4. However, complexes with o-substituted Ar ligands do not react with 02, reportedly due to steric shielding of the metal centre.329... 

Other simple, 6-coordinate M111 compounds include the Tc(dike)3 and analogous monothio dike molecules. With very bulky ArS ligands (e.g., Ar = 2,4,6-trisisopro-pylphenyl), 5-coordinate Tc(SAr)3L2 complexes have been obtained.43... 

Androgen receptor (AR) Ligand-induced homodimer Testosterone palindromic inverted repeat... 

Phosphines, Phosphites, and Combinations with Other or-Donor/ar-Ligands... 

A further significant development was the synthesis of a fluorescent form of the hydrophilic P-AR ligand CGP12177 (32). These authors synthesized both a BODIPY and FITC version of CGP12177 and found that the BODIPY form exhibited similar binding characteristics when compared with the native form. Our own work with both these compounds also observed significant photo-bleaching of the FITC form the BODIPY form was far more stable under fluorescence excitation. 

Pfizer patented a series of AR ligands which are analogs of the Ligand Pharmaceuticals 6-quinolinone templates. These AR ligands are of three templates (i) 6-sulfonamide pyridones [132], (ii) benzyl urea pyridones [133] and (iii) benzyl coumarins [134] that appear to be weak affinity (micromolar) antagonists which are illustrated as representative examples 41, 42 and 43, respectively, in Figure 8.10. Conspicuously absent from these quinolinones is the aniline moiety, which may explain the low affinity and lack of agonist activity. 

Figure 8.10 Quinolinone (pyridone), coumarin and other fused ring SARMs. Tetra-, tri- and bicyclic AR ligands are organized from left to right.

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