H

Figure 16 Diphenylquinoline estrogen receptor ligands.

binds to estrogen receptor in a manner where the C5 aryl ring mimics the A-ring of E2. A similar binding mode was seen previously for the pyrazole series.

Interestingly, both the pyrazole and furan ligands substituted with the basic side chain appear to bind in a different mode to the unsubstituted, parent molecules. In the case of furan and pyrazole agonists such as 17, it appears that the C2 phenol corresponds to the E2 A-ring. Compound 29 was subsequently examined in a cotransfection assay using HEC-1 cells and was found to be a full antagonist at ERa at 0.1 mmol L_ 1 but had no effect on transcription through ERb at this concentration.

Two series of diphenyl quinolines and isoquinolines were prepared where the aminoalkyl basic side chain was designed to occupy a different spatial location compared to typical SERMs such as tamoxifen and raloxifene (Figure 16).78 Binding to ERa was determined with cytosolic estrogen receptor from MCF-7 cells. The compounds, in general, proved to have weak affinity and, as a class, tended to be cytotoxic. Interestingly, compounds that possessed a phenolic group (e.g., 30) failed to exhibit any binding affinity. Molecular modeling studies attributed this to the fact that the 3-phenyl ring most likely does not occupy the same binding pocket as the E2 A-ring and hence lacks the electrostatic interaction with Glu-353 and Arg-394. Estrogenicity and antiestrogenicity were measured by progesterone receptor induction in MCF-7 cells. Compound 31, which was shown to bind ERa weakly, was demonstrated to possess weak antiestrogenic activity, and antiproliferative and cytotoxic effects in MCF-7 cells (IC50 = 7.1 mmolL"1). Compounds lacking the basic side chain displayed minimal estrogen receptor-mediated activity.

Although the 2-phenylindole moiety has been known for some time to be a suitable core for the generation of estrogen receptor ligands,79 recent progress has resulted in the identification of two SERMs which are currently in clinical trials.80 The compounds (32 and 33), which differ only in the nature of the basic side chain, possess a more rigid side chain than the previously disclosed structures (Figure 17).

Both compounds display modest a-selectivity and have reasonable binding affinity for ERa (IC50 <25nmolL_ 1) and ERb (IC50 <90nmolL"1). The more rigid side chain clearly plays a positive role in blocking transcrip-tional activity. The compounds were shown to be potent antagonists in MCF-7 cells (IC50 <5 nmol L_ 1). The indoles were also examined for uterotrophic activity in the 3-day immature rat model. Both compounds showed no significant increase in uterine wet weight when dosed alone subcutaneously for 3 days and, in antagonist mode, completely inhibited E2-induced uterine wet weight gain. In a 6-week OVX rat bone assay, azepine derivative (33) was shown to prevent bone loss in the proximal tibia at a dose of 0.3 mgkg _ 1 per day. Total cholesterol was also reduced in this assay at a 0.1 mgkg_ 1 per day dose. Indole (33) was also tested in a rat hot-flash assay to assess the ability of the compound to agonize or antagonize the vasomotor response.81 As was observed for other SERMs such as raloxifene, 33 is an estrogen antagonist in this assay. However, the antagonism was only significant above a 1mgkg_ 1 dose, which is threefold higher than the bone-sparing dose of 0.3 mgkg_ 1, thus suggesting that a therapeutic window may exist for treating osteoporosis without inducing hot flashes. Indole (33), which has been named bazedoxifene, is currently in phase III trials for the treatment of osteoporosis and pipindoxifene (32) has been in phase II trials for the treatment of

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