Pharmacological characterization of AC-262536, a novel selective androgen receptor modulator

Piu, Fabrice; Gardell, Luis R.; Son, Thomas; Schlienger, Nathalie; Lund, Birgitte W.; Schiffer, Hans H.; Vanover, Kimberly E.; Davis, Robert E.; Olsson, Roger; Bradley, Stefania Risso

doi:10.1016/j.jsbmb.2007.11.001

Cited by 24 publications

(17 citation statements)

References 25 publications

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“…The compound stimulated the growth of the levator ani muscle and suppressed elevated LH levels. AC-262536 has weak androgenic effects compared with testosterone (Piu et al, 2008).…”

Section: Selective Androgen Receptor Modulatorsmentioning

confidence: 99%

Nuclear Receptors and Their Selective Pharmacologic Modulators

et al. 2013

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“…The compound stimulated the growth of the levator ani muscle and suppressed elevated LH levels. AC-262536 has weak androgenic effects compared with testosterone (Piu et al, 2008).…”

Section: Selective Androgen Receptor Modulatorsmentioning

confidence: 99%

Nuclear Receptors and Their Selective Pharmacologic Modulators

et al. 2013

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“…Very recently, a promising novel SARM of this type was discovered, 4-(3-hydroxy-8-aza-bicyclo[3.2.1]octyl)-napthalene-1-carbonitrile (AC-262536) [234]. In both in vitro and in vivo, AC-262536 is a partial androgen agonist that induces ~70% of maximal testosterone effects but shows only minimal androgenic activity (<20% maximal testosterone effects) on prostate and seminal vesicles [234].…”

Section: Neuroactive Selective Androgen Recep-tor Modulatorsmentioning

confidence: 99%

The Potential Use of Hormone-Based Therapeutics for the Treatment of Alzheimers Disease

Carroll¹,

Rosario²

2012

CAR

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In both men and women, age-related loss of sex steroid hormones has been linked to an increased risk for Alzheimer's disease (AD). The primary female hormone estrogen, and the primary male hormone testosterone have numerous protective effects in the brain relevant to the prevention of AD such as the promotion of neuron viability, reduction of β- amyloid accumulation and alleviation of tau hyperphosphorylation. Therefore it has been hypothesized that the precipitous loss of these hormones either through menopause or normal aging, can increase susceptibility to AD pathogenesis. This review will discuss the basic science research and epidemiological evidence largely supporting this hypothesis, as well as the estrogen-based hormone therapy clinical findings that have recently shed doubt on this theory. The complications associated with estrogen-based hormone therapy such as the inclusion of a progestogen, hormone responsiveness with age, and natural vs. synthetic hormones will be discussed. Further, we will outline the cancer risks facing both estrogen and testosterone-based hormone therapy. Most importantly, this review will discuss the present and future strategies to translate the neuroprotective properties of sex steroid hormones into safe and efficacious treatments for AD. One of the most promising translational tools thus far may be the development of selective estrogen and androgen receptor modulators. However, additional research is needed to optimize these and other translational tools towards the successful use of hormone therapies in both men and women to delay, prevent, and or treat AD.

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“…The plateau in prostate activity is unique among androgens and demonstrates a true partial agonist activity. Other SARMs have varying degrees of tissue-selective activity, but some increase prostate weight above eugonadal levels at high doses Ostrowski et al, 2007), whereas others have been evaluated over a very narrow dose range, making it difficult to assess the partial agonist activity (Diel et al, 2008;Page et al, 2008;Piu et al, 2008). Pharmacokinetic data from these studies have not been published, making it difficult to confirm that partial agonist activity is not an artifact of saturated compound exposure.…”

Section: Discussionmentioning

confidence: 99%

“…The ideal SARM would be orally available without stimulatory effects in prostate and skin while maintaining the beneficial effects of androgen treatment. Multiple SARMs have been described, but the precise mechanism responsible for their tissue-selective activity is unknown (Yin et al, 2003;Martinborough et al, 2007;Ostrowski et al, 2007;Page et al, 2008;Piu et al, 2008). It has been postulated that the selectivity is the result of altered cofactor recruitment.…”

mentioning

confidence: 99%

“…The pharmacological activity has been described for several chemical series, but pharmacokinetic data have not been published (Hanada et al, 2003;Martinborough et al, 2007;Miner et al, 2007;Ostrowski et al, 2007;Diel et al, 2008;Piu et al, 2008). More extensive pharmacokinetic data have been published for the aryl propionamide analogs over a limited number of oral and intravenous doses (Kearbey et al, 2004;Chen et al, 2005;Kim et al, 2005).…”

mentioning

confidence: 99%

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Pharmacokinetics and Pharmacodynamics of LGD-3303 [9-Chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one], an Orally Available Nonsteroidal-Selective Androgen Receptor Modulator

Vajda¹,

López²,

Rix³

et al. 2008

J Pharmacol Exp Ther

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Selective androgen receptor modulators (SARMs) are a new class of molecules in development to treat a variety of diseases. SARMs maintain the beneficial effects of androgens, including increased muscle mass and bone density, while having reduced activity on unwanted side effects. The mechanisms responsible for the tissue-selective activity of SARMs are not fully understood, and the pharmacokinetic (PK)/pharmacodynamic (PD) relationships are poorly described. Tissue-specific compound distribution potentially could be a mechanism responsible for apparent tissue selectivity. We examined the PK/PD relationship of a novel SARM, LGD-3303 [9-chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[3,2-f]quinolin-7(6H)-one], in a castrated rat model of androgen deficiency.LGD-3303 has potent activity on levator ani muscle but is a partial agonist on the preputial gland and ventral prostate.LGD-3303 never stimulated ventral prostate above intact levels despite increasing plasma concentrations of compound. Tissue-selective activity was maintained when LGD-3303 was dosed orally or by continuous infusion, two routes of administration with markedly different time versus exposure profiles. Despite the greater muscle activity relative to prostate activity, local tissue concentrations of LGD-3303 were higher in the prostate than in the levator ani muscle.LGD-3303 has SARM properties that are independent of its pharmacokinetic profile, suggesting that the principle mechanism for tissue-selective activity is the result of altered molecular interactions at the level of the androgen receptor.

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Pharmacological characterization of AC-262536, a novel selective androgen receptor modulator

Cited by 24 publications

References 25 publications

Nuclear Receptors and Their Selective Pharmacologic Modulators

Nuclear Receptors and Their Selective Pharmacologic Modulators

The Potential Use of Hormone-Based Therapeutics for the Treatment of Alzheimers Disease

Pharmacokinetics and Pharmacodynamics of LGD-3303 [9-Chloro-2-ethyl-1-methyl-3-(2,2,2-trifluoroethyl)-3H-pyrrolo-[3,2-f]quinolin-7(6H)-one], an Orally Available Nonsteroidal-Selective Androgen Receptor Modulator

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