Pyrazole Ligands:  Structure−Affinity/Activity Relationships and Estrogen Receptor-α-Selective Agonists

Abstract

We have found that certain tetrasubstituted pyrazoles are high-affinity ligands for the estrogen receptor (ER) (Fink et al. Chem. Biol. 1999, 6, 205-219) and that one pyrazole is considerably more potent as an agonist on the ERalpha than on the ERbeta subtype (Sun et al. Endocrinology 1999, 140, 800-804). To investigate what substituent pattern provides optimal ER binding affinity and the greatest enhancement of potency as an ERalpha-selective agonist, we prepared a number of tetrasubstituted pyrazole analogues with defined variations at certain substituent positions. Analysis of their binding affinity pattern shows that a C(4)-propyl substituent is optimal and that a p-hydroxyl group on the N(1)-phenyl group also enhances affinity and selectivity for ERalpha. The best compound in this series, a propylpyrazole triol (PPT, compound 4g), binds to ERalpha with high affinity (ca. 50% that of estradiol), and it has a 410-fold binding affinity preference for ERalpha. It also activates gene transcription only through ERalpha. Thus, this compound represents the first ERalpha-specific agonist. We investigated the molecular basis for the exceptional ERalpha binding affinity and potency selectivity of pyrazole 4g by a further study of structure-affinity relationships in this series and by molecular modeling. These investigations suggest that the pyrazole triols prefer to bind to ERalpha with their C(3)-phenol in the estradiol A-ring binding pocket and that binding selectivity results from differences in the interaction of the pyrazole core and C(4)-propyl group with portions of the receptor where ERalpha has a smaller residue than ERbeta. These ER subtype-specific interactions and the ER subtype-selective ligands that can be derived from them should prove useful in defining those biological activities in estrogen target cells that can be selectively activated through ERalpha.

Estrogen anti-inflammatory activity in brain: A therapeutic opportunity for menopause and neurodegenerative diseases

“…Since their original description ( [163,216]) ERa and ERb selective modulators (SERMs) have been employed to dissect the relative contribution of each ER subtype and to obtain more potent responses devoid of toxic effects. The ERa selective ligand propyl pyrazole triol (PPT) provides neuroprotection and anti-inflammatory activities in brain in experimental models of neurodegenerative diseases, including ischemia [165], MPTP-induced neurotoxicity [52] and EAE ( [69,170]).…”

Differential Effects of Estrogen Receptor Alpha and Beta Specific Agonists on Social Learning of Food Preferences in Female Mice

“…In a first experiment, the ERa agonist 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT), which is 410 times more selective for ERa than ERb in mice (Stauffer et al, 2000), was used. Four groups were formed: a sesame oil (vehicle) control (n ¼ 22), and three doses of PPT, 0.025 mg/kg (n ¼ 21), 0.05 mg/kg (n ¼ 22), and 0.1 mg/kg (n ¼ 21).…”

Synthesis and biodistribution of fluorine-18-labeled fluorocyclofenils for imaging the estrogen receptor

“…The discovery that there are two ER subtypes, ERα and ERβ, having different tissue distributions, different biological roles, and different activity levels [19,20], has further stimulated the search for ER ligands that might act selectively on these subtypes [20], and has led to the development of the ERα-selective pyrazole PPT [21], as well as other furan, and pyrrole derivatives [22], and the ERβ-selective diarylpropionitrile DPN [23], as well as other cyclofenil, and tetrahydrochrysene derivatives ( Figure 1) [24,25]. Also of interest is the development of ER ligands that might be effective in imaging the ERs in a subtype-selective manner [26,27].…”