The Intracellular Receptor and Signal Transducers and Activators of Transcription Factor Superfamilies: Novel Targets for Small-Molecule Drug Discovery

Rosen, Jon; Aj, Day; Jones, Todd K.; Jones, Eric; Nadzan, Alex M.; Stein, Robert B.

doi:10.1021/jm00025a001

Cited by 78 publications

(29 citation statements)

References 28 publications

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“…Recent advances in understanding the mechanisms by which nuclear hormone receptors exert their effects on gene transcription have greatly enhanced the prospects for tissueselective regulation of these processes (1)(2)(3)(4). The recognition that the estrogen receptor (ER) may interact with more than one DNA response element, that these interactions may be mediated by various coactivators and corepressors, and that the nature of these interactions may be dependent on the specific ligand that is bound to the receptor allows for the possibility of ligand-based transcriptional control (5)(6)(7)(8).…”

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confidence: 99%

Molecular determinants of tissue selectivity in estrogen receptor modulators

Grese

Sluka

Bryant

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

225

160

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Interaction of the estrogen receptor͞ligand complex with a DNA estrogen response element is known to regulate gene transcription. In turn, specific conformations of the receptor-ligand complex have been postulated to influence unique subsets of estrogen-responsive genes resulting in differential modulation and, ultimately, tissue-selective outcomes. The estrogen receptor ligands raloxifene and tamoxifen have demonstrated such tissue-specific estrogen agonist͞antagonist effects. Both agents antagonize the effects of estrogen on mammary tissue while mimicking the actions of estrogen on bone. However, tamoxifen induces significant stimulation of uterine tissue whereas raloxifene does not. We postulate that structural differences between raloxifene and tamoxifen may influence the conformations of their respective receptor͞ligand complexes, thereby affecting which estrogen-responsive genes are modulated in various tissues. These structural differences are 4-fold: (A) the presence of phenolic hydroxyls, (B) different substituents on the basic amine, (C) incorporation of the stilbene moiety into a cyclic benzothiophene framework, and (D) the imposition of a carbonyl ''hinge'' between the basic amine-containing side chain and the olefin. A series of raloxifene analogs that separately exemplify each of these differences have been prepared and evaluated in a series of in vitro and in vivo assays. This strategy has resulted in the development of a pharmacophore model that attributes the differences in effects on the uterus between raloxifene and tamoxifen to a low-energy conformational preference imparting an orthogonal orientation of the basic side chain with respect to the stilbene plane. This three-dimensional array is dictated by a single carbon atom in the hinge region of raloxifene. These data indicate that differences in tissue selective actions among benzothiophene and triarylethylene estrogen receptor modulators can be ascribed to discrete ligand conformations.

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mentioning

confidence: 99%

Molecular determinants of tissue selectivity in estrogen receptor modulators

Grese

Sluka

Bryant

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

225

160

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“…A series of androgen receptor modulators based on 8H- [1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro.…”

Section: Introductionmentioning

confidence: 99%

“…1 The endogenous ligands for AR are the steroids testosterone (T) and dihydrotestosterone (DHT). When bound to AR, these ligands play important roles in sexual development and function, 2 and musculo-skeletal growth.…”

Section: Introductionmentioning

confidence: 99%

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Potent, nonsteroidal selective androgen receptor modulators (SARMs) based on 8H-[1,4]oxazino[2,3-f]quinolin-8-ones

Higuchi

Thompson

Chen

et al. 2007

Bioorganic & Medicinal Chemistry Letters

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A series of androgen receptor modulators based on 8H- [1,4]oxazino[2,3-f]quinolin-8-ones was synthesized and evaluated in an androgen receptor transcriptional activation assay. The most potent analogues from the series exhibited single-digit nanomolar potency in vitro. Compound 18h demonstrated full efficacy in the maintenance of muscle weight, at 10 mg/kg, with reduced activity in prostate weight in an in vivo model of androgen action.The androgen receptor (AR) is a member of the intracellular receptor superfamily of liganddependent transcription factors. 1 The endogenous ligands for AR are the steroids testosterone (T) and dihydrotestosterone (DHT). When bound to AR, these ligands play important roles in sexual development and function, 2 and musculo-skeletal growth. 3 Steroidal androgen therapy is effective for the treatment of androgen insufficiency. However, the broader use of these androgens for additional treatments, such as osteoporosis or frailty, is limited by undesirable AR-mediated effects, such as prostatic hypertrophy and hirsutism. A selective androgen receptor modulator (SARM), with full anabolic activity but reduced impact on the undesirable effects could have a large role on endocrine therapies to treat muscle wasting and osteoporosis. 4 Early studies on modified androgens explored alkylation at C-17, as in fluoxymesterone (1 , Figure 1). 5 However, compounds from this general class are associated with potential liver toxicity. 2 Recent publications in the area of nonsteroidal androgens is indicative of the high level in discovering novel safe, effective anabolic agents (2, 3). [6][7][8] Our continued interest in SARMs is based on scaffolds derived from quinolin-2-ones (4 and 5). 9,10 During the course of our studies on 7H-[1,4]oxazino[3,2-g]quinolin-7-ones (5a), we isolated as a minor byproduct of the Knorr quinolone reaction 11 regioisomer (6a, <5% yield, Scheme 1) which fortuitously possessed AR agonist activity in a transcriptional activation assay (78% agonist efficacy, 5 nM). Investigations into the scaffold led to a series of novel androgens derived from 8H-[1,4]oxazino[2,3-f]quinolin-8-ones (6). The lead compound from this series, 18h, demonstrated full efficacy in the maintenance of levator ani weight (LA) muscle, an anabolic endpoint in a castrated mature rat model.Our previous investigations of quinolinone scaffolds 4 and 5 revealed that the regions proximal to the tertiary amine group strongly affected AR activity. Consequently, we sought to probe

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“…3 The retinoid receptors belong to the superfamily of intracellular nuclear receptors, which function to regulate gene transcription. 4 They are divided into two families of homologous receptors, the retinoic acid receptors (RARs) and the retinoid x receptors (RXRs), each divided into three sub-types a, b and g encoded by a single gene. 5 RXR has long been recognized to both form homodimers and to heterodimerize with various other nuclear receptors, such as RAR, TR, VDR, NGFIB, LXR, FXR and PPARs.…”

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confidence: 99%