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  • br The orphan estrogen related receptor exists as three subt

    2019-08-06


    The orphan estrogen-related receptor exists as three subtypes (ERRα, ERRβ, and ERRγ) in the human genome. ERRα is expressed in metabolically active tissues such as muscle and adipose. ERRγ is expressed in the spinal cord and CNS. ERRβ appears to play a role in development, as postnatal expression is highly restricted, being detected only at low levels in the liver, stomach, skeletal muscle, heart, and kidney. These orphan nuclear receptors are most closely related in sequence to the classical apexbio dilution reviews receptors ERα and ERβ but do not bind estradiol or other related steroidal estrogens. In contrast, the ERRs show varying levels of constitutive transcriptional activity, and no endogenous ligand has been identified to date. Notably, the fasting-induced cofactor PGC-1α has been reported as an endogenous protein ligand for the ERRs, raising the possibility that the receptors may not be regulated by small molecules. Despite these observations, two lines of evidence demonstrate that the ERRs have the potential to be chemically tractable. First, inverse agonists (antagonists of constitutive ERR activity) have been identified: the potent estrogen receptor antagonist 4-hydroxytamoxifen (, 4-OHT) is an inverse agonist of ERRγ. Second, we recently reported the acyl hydrazone GSK4716 ( as a submicromolar ERRγ/β agonist with efficacy comparable to that of PGC-1α and greater than 50-fold binding selectivity over the classical estrogen receptors. Despite these advances, the development of an ERRγ inverse agonist with selectivity against the classical estrogen receptors remains unrealized. With the goal of developing a selective ERRγ inverse agonist, we focused on the 4-OHT () template because of its affinity for ERRγ and its inverse agonist functional profile. The key challenge was that has higher affinity for ERα than ERRγ. A number of analogs of and their associated SAR with the classical estrogen receptor have been reported. Combining this knowledge with analysis of the X-ray crystal structures of bound to the ligand binding domains of ERRγ and ERα provided a basis for design of ERRγ-selective ligands. The unliganded ERRγ LBD crystal structure contains a small (220Å) ligand binding pocket (LBP), but reorganizes to accommodate the binding of (). Although the sequence identity between ERα and ERRγ is only 36%, the residues that line the first shell of the ligand binding pocket have a high degree of identity between ERRγ and ERα, and many common elements critical for ligand recognition are conserved in the two structures. Notably, the glutamate and arginine residues in ERα (and ERβ) that form the hydrogen bond interaction with the phenolic A-ring of estradiol are found in all three of the ERRs (ERRγ E275 and R316). The basic side chain of makes a Coulombic interaction with an aspartate (ERα D351; ERRγ D273). In contrast to the similarity between ERRγ and ERα in the first shell of the ligand binding pocket, a key difference is located proximal to the ethyl group of 4-OHT. A pair of phenylalanine residues (F404 and F425) in ERα corresponds to a tyrosine and asparagine (Y326 and N346) in ERRγ. The distances from the ethyl terminal carbon to the oxygens in Y326 and N346 are 3.2 and 4.3Å, respectively, suggesting that these residues may be accessible by extension of the ethyl side chain. We set out to exploit these residues in the design of analogs with targeted selectivity for ERRγ over ERα. Accordingly, we designed 4-OHT analogs with extended ethyl side chains bearing polar functionality capable of interactions with the Y-N pair in ERRγ and unfavorable interactions with the hydrophobic phenylalanines in ERα. Synthesis of the 4-OHT analogs was accomplished using an established methodology (). The triarylethylene intermediates were synthesized in three steps following the procedure of Gauthier and coworkers. Monoprotection of commercially available 4,4′-dihydroxybenzophenone with pivaloyl chloride followed by McMurry coupling with substituted acetophenones yielded triarylethylenes; stereoselectivity of the coupling favored the desired isomer, with typical : ratios >4:1 as determined by NOE measurements. Mitsunobu reaction with ,-dimethylaminoethanol was employed for installation of the basic side chain. With R=(CH)Cl, functionalization to the 4-OHT analogs was accomplished by nucleophilic displacement of the halide with RR′NH, MeS, CN, or N followed by hydrolysis of the pivaloate ester. Alternatively, the intermediates with R=(CH)COMe could be directly reduced to the desired alcohol compounds with concomitant pivaloate deprotection. Compounds were purified to configurational homogeneity prior to in vitro profiling.