Pyrazolo[1,5-a]pyrimidines:  Estrogen Receptor Ligands Possessing Estrogen Receptor β Antagonist Activity

Abstract

In our search for novel subtype-selective estrogen receptor (ER) ligands, we have examined various heterocyclic units as core structural elements. Here, we have investigated the fused, bicyclic pyrazolo[1,5-a]pyrimidine core, which is a system that allows for analogues to be readily assembled in a library-like fashion. This series of pyrazolo[1,5-a]pyrimidine ER ligands provided us with a new pharmacological profile for an ER ligand: compounds that are passive on both ERs, with a distinct potency selectivity in favor of ERbeta. The most distinctive ligand in this series, 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine, was 36-fold selective for ERbeta in binding. Curiously, on the basis of molecular modeling, the ERbeta binding selectivity of compounds in this series appears to be derived from differing orientations that they adapt in the ligand binding pockets of ERalpha vs ERbeta. In transcription assays this pyrazolopyrimidine was fully effective as an ERbeta antagonist while exhibiting no significant activity on ERalpha. Thus, this ligand functions as a potency- and efficacy-selective ERbeta antagonist that would abrogate estrogen action through ERbeta with minimal effects on its activity through ERalpha; as such, it could be used to study the biological function of ERbeta.

Catalyst‐Switchable Regiocontrol in the Direct Arylation of Remote CH Groups in Pyrazolo[1,5‐a]pyrimidines

“…[7] We report herein the catalyst-controlled switching in regioselectivity between the remote positions C3 and C7 of pyrazolo[1,5-a]pyrimidine (1; Figure 1). We chose this motif [8] because it forms the core of ar ange of biologically active compounds.S pecifically,a ryl-substituted pyrazolo[1,5-a]pyrimidines show antitumor [9] and anti-inflammatory properties, [10] have been examined as hepatitis Cvirus inhibitors and estrogen receptor ligands, [11,12] and are found in the approved sedative agents zaleplon and indiplon as well as in the anxiolytic agent ocinaplon.We began our study with the optimization of the coupling of compound 1 with bromobenzene in the presence of av ariety of palladium sources,w ith and without phosphines, changing solvents,bases,additives,and conditions.The results from this survey are summarized in the Supporting Information, and Scheme 2highlights the optimized conditions. Theu se of the monodentate phosphine ligand SPhos proved crucial to achieving site selectivity at C7, giving the desired product 2a in good yield.…”

“…[7] We report herein the catalyst-controlled switching in regioselectivity between the remote positions C3 and C7 of pyrazolo [1,5-a]pyrimidine (1; Figure 1). We chose this motif [8] because it forms the core of ar ange of biologically active compounds.S pecifically,a ryl-substituted pyrazolo [1,5-a]pyrimidines show antitumor [9] and anti-inflammatory properties, [10] have been examined as hepatitis Cvirus inhibitors and estrogen receptor ligands, [11,12] and are found in the approved sedative agents zaleplon and indiplon as well as in the anxiolytic agent ocinaplon.…”

Bisphenol A enhances kisspeptin neurons in anteroventral periventricular nucleus of female mice

“…MPP (50 nmol/ mouse; Harrington et al 2003), PHTPP (50 nmol/mouse; Harrington et al 2003, Compton et al 2004, and p234 (5 nmol/mouse; Roseweir et al 2009) were injected (i.c.v., 3 ml/mouse) at 30 min before injection of BPA using a stepper-motorized microsyringe at a rate of 0.2 ml/min. The drugs were prepared freshly on the day of experiment.…”

Synthesis of Novel Nitro-substituted Triaryl Pyrazole Derivatives as Potential Estrogen Receptor Ligands

“…The latter may vary in length and size, including a plethora of -fused and nonfused-carbocyclic and heterocyclic ring systems [2][3][4].…”