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Several groups have disclosed ERb-selective ligands in the patent literature. A group at AstraZeneca has claimed a series of genistein analogs with impressive binding selectivity for ERb (Figure 29).106 For example, the genistein analog (78) with an n-propyl substituent at the C3' position of the isoflavone ring system has a reported binding Ki of 0.75 nmol L _ 1 at ERa and > 3000 nmol L _ 1 at ERa. Another disclosure from the same group claims a series of analogs

in which the C5 hydroxyl of the genistein isoflavone ring system has been replaced by halogens, nitrile, and thiomethyl.107 The chloro-analog (79) has a binding affinity of 4.3 nmol L— 1 for ERb with a selectivity of 139-fold.

Researchers at AstraZeneca have also disclosed a series of benzimidazoles108 of generic structure 80 as selective ERb ligands (Figure 30). The compounds are reported to have binding affinity of 15-2000 nmol L— 1 with selectivity for ERb of 50-0.5. The compounds were also assayed for functional activity in human embryonic kidney cells (HEK 293) transiently transfected with either ERa or ERb and a b-galactosidase reporter. They have reported EC50 =1-1200 nmol L — 1 with selectivity for ERb of 250-0.005. Related series of benzoxazoles and benzothiazoles109 have also been disclosed (Figure 30). Benzoxazole (81) is reported to have a binding affinity of 1.7 nmol L— 1 with a selectivity for ERb of 10-fold and is a full agonist (EC50 = 1.2 nmol L— 1) with selectivity for ERb of 52-fold. A related series of isoquinolines and isoindolines110 has also been disclosed (Figure 30). Isoquinoline (82) is reported to have a binding affinity of 8 nmol L — 1, with a selectivity for ERb of sevenfold and is a full agonist (EC50 = 36 nmol L — 1 for ERb and 28 nmol L — 1 for ERa). Isoindoline (83) is reported to have a binding affinity of 55 nmol L — 1 with a selectivity for ERb of 3.5-fold but is only a partial agonist (EC50 = 161 nmol L— 1, 77% relative efficiency for ERb and EC50 = 192 nmol L — 1, 60% relative efficiency for ERa).

A group from Akzo Nobel have disclosed a series of chromane derivatives of general structure (84: Figure 31).111 Chromane (85) is reported to have a potency ratio > 10% relative to E2 and a selectivity for ERb > 30-fold. The same group has also disclosed a series of tetracyclic compounds of general structure 86.112 Tetracycle (87) has a potency transactivation of ERb > 10% relative to E2 and a selectivity for ERb > 30-fold. In a related filing the same tetracyclic compounds (88) are adorned with a basic side chain to provide ERb antagonists.113 Tetracycle (89) is reported to have good ERb antagonist activity (>100% compared to ICI 164,384).

Merck has disclosed tetrahydrofluorenones of general structures 90 and 92 (Figure 32).11 Compounds of general structure 90 have binding affinities to ERa in the range of IC50 = 2.8-5 625 nmol L — 1 and to ERb in the range of IC50 = 0.6-126 nmol L— 1. Compounds of general structure 92 have binding affinities to ERa in the range of IC50 = 36->10 000 nmol L — 1 and to ERb in the range of IC50 = 1.4-283 nmol L — 1.

Recent advances in ERb scaffolds include 2-phenylnaphthalenes115 (WAY-202196) and benzisoxazoles116 (ERB-041), which are being investigated for chronic inflammatory diseases (Figure 33).

7.07.5.1.8 Steroid-derived modulators

The estrogen platform has been used extensively to study the structure and function of the estrogen receptor. In fact, the attachment of the appropriate functionality on to the steroid backbone has led to the development of SERMs as well as pure antagonists, affinity labels, and other important tools for understanding estrogen-mediated pharmacology. The effects of substitution on the estrogen nucleus have been reviewed in depth recently, leading to the derivation of a binding site model.117

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