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

  title={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},
  author={Eric G. Vajda and Francisco J. L{\'o}pez and Peter J. Rix and Robert Hill and Yanling Chen and Kyoung Jin Lee and Zhihong O’Brien and William Y. Chang and Martin D. Meglasson and Yong-Hee Lee},
  journal={Journal of Pharmacology and Experimental Therapeutics},
  pages={663 - 670}
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… 

Figures and Tables from this paper

1-(2-Hydroxy-2-methyl-3-phenoxypropanoyl)indoline-4-carbonitrile derivatives as potent and tissue selective androgen receptor modulators.

We present a novel series of selective androgen receptor modulators (SARMs) which shows excellent biological activity and physical properties.

Design, synthesis, and biological evaluation of nonsteroidal cycloalkane[d]isoxazole-containing androgen receptor modulators.

The design, preparation, and systematic evaluation of a novel cycloalkane[d]isoxazole pharmacophoric fragment-containing androgen receptor (AR) modulators are reported, and the most potent compound, 6a maintains its antiandrogenic activity with AR mutants W741L and T877A commonly observed and activated by bicalutamide and hydroxyflutamide, respectively, in prostate cancer patients.

A selective androgen receptor modulator SARM‐2f activates androgen receptor, increases lean body mass, and suppresses blood lipid levels in cynomolgus monkeys

It is demonstrated that SARM‐2f exerted anabolic effects and produced a lipid profile that differed from that produced by testosterone in monkeys, suggesting that the drug might be useful for diseases such as sarcopenia.

Pharmacological characterization of an imidazolopyrazole as novel selective androgen receptor modulator

Nonsteroidal selective androgen receptor modulators (SARMs): dissociating the anabolic and androgenic activities of the androgen receptor for therapeutic benefit.

This Award Address attempts to chronicle the landmark discoveries, organize the SARM landscape into clinically relevant bins, and provide insight into the clinical prospects for SARMs.

Deciphering the selective androgen receptor modulators paradigm

The aim of the present paper is to summarize the current standing of research and development of SARMs and plausible molecular mechanisms underlying the potential for selective modulation of androgen receptor (AR) by different ligands and provides an update on SARM discovery paradigms for preclinical evaluations.

Recent advances in the development of selective androgen receptor modulators

A new class of molecules targeting androgen receptors called selective androgen receptor modulators is being developed, analogous to the clinically successful and at present marketed selective estrogen receptors modulators.

Recent developments in antiandrogens and selective androgen receptor modulators



Pharmacokinetics of S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro- 3-trifluoromethyl-phenyl)-propionamide in rats, a non-steroidal selective androgen receptor modulator

The pharmacokinetics and oral bioavailability of S-4 indicate that it is an excellent candidate for clinical development and rapidly absorbed, slowly cleared, and has a moderate volume of distribution in rats.

The Para Substituent of S-3-(Phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamides Is a Major Structural Determinant of in Vivo Disposition and Activity of Selective Androgen Receptor Modulators

Analysis of the area under the concentration-time curve-response relationship demonstrated that the discrepancy between in vitro and in vivo pharmacological activity of these halogen-substituted SARMs was due to differences in systemic exposure rather than intrinsic pharmacological action.

Substituted 6-(1-pyrrolidine)quinolin-2(1H)-ones as novel selective androgen receptor modulators.

The discovery of a new class of orally available selective androgen receptor modulators is described, which showed excellent anabolic activity in muscle with reduced effect on the prostate in a rat model of hypogonadism.

A Selective Androgen Receptor Modulator for Hormonal Male Contraception

These studies show that C-6 mimicked the in vivo pharmacologic and endocrine effects of testosterone while maintaining the oral bioavailability and tissue-selective actions of nonsteroidal SARMs.

Ockham's razor and selective androgen receptor modulators (SARMs): are we overlooking the role of 5alpha-reductase?

The tissue-specific expression of 5alpha-reductase might provide a simple explanation for this puzzle of the SARM story, and lead compounds with much improved specificity for AR, in vivo pharmacokinetic profiles, and higher degree of tissue selectivity have entered clinical development.

Pharmacodynamics of Selective Androgen Receptor Modulators

Compounds S-1 and S-4 were identified as SARMs with potent and tissue-selective in vivo pharmacological activity, and represent the first members of a new class of SAR Ms with selective anabolic effects.

Tissue selectivity of the anabolic steroid, 19-nor-4-androstenediol-3beta,17beta-diol in male Sprague Dawley rats: selective stimulation of muscle mass and bone mineral density relative to prostate mass.

3beta,19-NA increases muscle and bone mass without significant stimulation of prostate growth, suggesting it may have some properties of a steroidal selective androgen receptor modulator.

Bone anabolic effects of S-40503, a novel nonsteroidal selective androgen receptor modulator (SARM), in rat models of osteoporosis.

Collectively, this novel compound served as a prototype for SARMs, which had unique tissue selectivity with high potency for bone formation and lower impact upon sex accessory tissues.

Pharmacological and x-ray structural characterization of a novel selective androgen receptor modulator: potent hyperanabolic stimulation of skeletal muscle with hypostimulation of prostate in rats.

The potent oral activity and tissue selectivity exhibited by BMS-564929 are expected to yield a clinical profile that provides the demonstrated beneficial effects of T in muscle and other tissues with a more favorable safety window.