Switching androgen receptor antagonists to agonists by modifying C-ring substituents on piperidino[3,2-g]quinolinone

Zhi, Lin; Tegley, Christopher M.; Marschke, Keith B.; Jones, Todd K.

doi:10.1016/s0960-894x(99)00119-5

Cited by 61 publications

(48 citation statements)

References 9 publications

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“…3), respectively, which could explain the relatively high binding affinity of LG121071. Comparing the structure of LG120907 (antagonist, Table I) and LG121071 (agonist, Table III), it is clear that C-ring substituents play an important role in determining the agonist or antagonist activity in tri-cyclic quinoline molecules (51). The A-ring and B-ring in LGD2226 may very likely mimic the steroid skeleton plane in a similar way as LG121071, while it is unclear if one of the trifluoroethyl groups mimics the 17β-OH group in testosterone.…”

Section: Bothmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

2006

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Testosterone and structurally related anabolic steroids have been used to treat hypogonadism, muscle wasting, osteoporosis, male contraception, cancer cachexia, anemia, and hormone replacement therapy in aging men or age-related frailty; while antiandrogens may be useful for treatment of conditions like acne, alopecia (male-pattern baldness), hirsutism, benign prostatic hyperplasia (BPH) and prostate cancer. However, the undesirable physicochemical and pharmacokinetic properties of steroidal androgen receptor (AR) ligands limited their clinical use. Nonsteroidal AR ligands with improved pharmacological and pharmacokinetic properties have been developed to overcome these problems. This review focuses on the pharmacokinetics, metabolism, and pharmacology of clinically used and emerging nonsteroidal AR ligands, including antagonists, agonists, and selective androgen receptor modulators.

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Section: Bothmentioning

confidence: 99%

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

2006

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“…Recently, a series of nonsteroidal compounds based on tricyclic quinolinones (Fig. 3A) were shown to produce AR agonist activity Hamann et al, 1999;Higuchi et al, 1999;Zhi et al, 1999). Because the quinolinone skeleton is structurally different from the previously discussed pharmacophores, we were interested to determine whether hybrids of these two sets of lead structures bound to the AR and elicited agonist activity.…”

Section: Structure-activity Relationships Of Nonsteroidal Ar Ligands 215mentioning

confidence: 99%

Key Structural Features of Nonsteroidal Ligands for Binding and Activation of the Androgen Receptor

et al. 2003

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The purposes of the present studies were to examine the androgen receptor (AR) binding ability and in vitro functional activity of multiple series of nonsteroidal compounds derived from known antiandrogen pharmacophores and to investigate the structure-activity relationships (SARs) of these nonsteroidal compounds. The AR binding properties of sixty-five nonsteroidal compounds were assessed by a radioligand competitive binding assay with the use of cytosolic AR prepared from rat prostates. The AR agonist and antagonist activities of highaffinity ligands were determined by the ability of the ligand to regulate AR-mediated transcriptional activation in cultured CV-1 cells, using a cotransfection assay. Nonsteroidal compounds with diverse structural features demonstrated a wide range of binding affinity for the AR. Ten compounds, mainly from the bicalutamide-related series, showed a binding affinity superior to the structural pharmacophore from which they were derived. Several SARs regarding nonsteroidal AR binding were revealed from the binding data, including stereoisomeric conformation, steric effect, and electronic effect. The functional activity of high-affinity ligands ranged from antagonist to full agonist for the AR. Several structural features were found to be determinative of agonist and antagonist activities. The nonsteroidal AR agonists identified from the present studies provided a pool of candidates for further development of selective androgen receptor modulators (SARMs) for androgen therapy. Also, these studies uncovered or confirmed numerous important SARs governing AR binding and functional properties by nonsteroidal molecules, which would be valuable in the future structural optimization of SARMs.

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“…Moreover, nonsteroidal ligands allow greater flexibility in structural modifications for optimal physicochemical, pharmacokinetic, and pharmacological properties. For the AR, nonsteroidal antagonists (antiandrogens) are now used clinically (McLeod, 1993); however, nonsteroidal agonists (androgens) have just recently been reported by our laboratories as well as others (Dalton et al, 1998;Edwards et al, 1998;Edwards et al, 1999;Hamann et al, 1999;Higuchi et al, 1999;Zhi et al, 1999) and are still in the early stages of drug discovery. Given the advantages of known nonsteroidal modulators of steroid receptors, the discovery of nonsteroidal androgens provides an opportunity for the development of a new generation of androgens with improved clinical therapeutic index.…”

mentioning

confidence: 98%

Pharmacology, Pharmacokinetics, and Metabolism of Acetothiolutamide, a Novel Nonsteroidal Agonist for the Androgen Receptor

Yin¹,

Xu²,

He³

et al. 2002

J Pharmacol Exp Ther

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The present study characterized the in vitro androgen receptor (AR) binding affinity, in vitro and in vivo pharmacological activity, and in vivo pharmacokinetics and metabolism of acetothiolutamide, a nonsteroidal AR ligand. AR binding was determined by a competitive binding assay. In vitro AR agonist activity was examined by a cotransfection assay. Acetothiolutamide displayed high AR binding affinity (K i ϭ 4.9 Ϯ 0.2 nM) and full agonist activity in the in vitro studies. Next, the androgenic, anabolic, and antiandrogenic activity of acetothiolutamide was evaluated in a castrated immature rat model. In this animal model, acetothiolutamide exhibited an overall negligible androgenic effect, but a statistically significant anabolic effect at high subcutaneous doses. Also, acetothiolutamide demonstrated a noticeable antiandrogenic effect in castrated rats supplemented with testosterone propionate. To understand the causes for the observed disparity between in vitro and in vivo activities, pharmacokinetics and metabolism of acetothiolutamide were studied in male Sprague-Dawley rats. Acetothiolutamide was rapidly cleared from rat plasma (clearance of about 45 ml/min/kg) in a concentration-independent manner after i.v. dosing. Acetothiolutamide was completely absorbed after subcutaneous administration, but not bioavailable after oral dose. In the metabolism study, the unchanged molecule and its metabolites in urine and fecal samples were detected by highperformance liquid chromatography-mass spectrometry. The structures of major metabolites were elucidated with liquid chromatography-tandem mass spectrometry. After i.v. administration, acetothiolutamide was excreted in urine and feces as unchanged drug and a variety of metabolites. Oxidation, hydrolysis, and sulfate conjugation of phase I metabolites were the major metabolic pathways of acetothiolutamide in rats. Overall, the high plasma clearance of acetothiolutamide, due to its extensive hepatic metabolism, likely contributed to its lack of androgenic activity in vivo.

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Switching androgen receptor antagonists to agonists by modifying C-ring substituents on piperidino[3,2-g]quinolinone

Cited by 61 publications

References 9 publications

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

Pharmacokinetics and Pharmacodynamics of Nonsteroidal Androgen Receptor Ligands

Key Structural Features of Nonsteroidal Ligands for Binding and Activation of the Androgen Receptor

Pharmacology, Pharmacokinetics, and Metabolism of Acetothiolutamide, a Novel Nonsteroidal Agonist for the Androgen Receptor

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