17α-Alkynyl 3α, 17β-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism

@article{Ahlem201017Alkynyl31,
  title={17$\alpha$-Alkynyl 3$\alpha$, 17$\beta$-androstanediol non-clinical and clinical pharmacology, pharmacokinetics and metabolism},
  author={Clarence N. Ahlem and Michael R. Kennedy and Theodore M. Page and David Bell and Evelyne Delorme and Sonia Villegas and Christopher L Reading and Steven K. White and Dwight R. Stickney and James M. Frincke},
  journal={Investigational New Drugs},
  year={2010},
  volume={30},
  pages={59-78}
}
Summary17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235, Apoptone) is an orally bioavailable synthetic analogue of 3β-androstanediol, that is active in rodent models of prostate and breast cancer, and is in Phase IIa clinical trials for the treatment of early- and late-stage prostate cancer. In preparation for clinical studies, nuclear hormone receptor and P450 interactions for HE3235 and major metabolites were characterized in vitro, and pharmacokinetics and metabolite profiles were studied in… 
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References

SHOWING 1-10 OF 36 REFERENCES
Inhibition of androstenediol-dependent LNCaP tumour growth by 17α-ethynyl-5α-androstane-3α, 17β-diol (HE3235)
TLDR
The identification of a novel androstane steroid, HE3235 (17α-ethynyl-5α-androstan-3α, 17β-diol), with significant inhibitory activity for AED-stimulated LNCaP proliferation, which suggests that this compound may be of clinical use in castration-resistant prostate cancer.
CYP7B Generates a Selective Estrogen Receptor β Agonist in Human Prostate
TLDR
7α-Hydroxylation was the major metabolic fate of DHEA in human prostate and it is shown that human prostate epithelial cells together with estrogen receptor β (ERβ) were localized in the epithelial Cells together with testosterone and 5α-dihydrotestosterone.
CYP7B generates a selective estrogen receptor beta agonist in human prostate.
TLDR
This study suggests that CYP7B catalyzes oxysterol 7alpha-hydroxylation within the human prostate epithelium, and may be a novel regulator of the androgens/estrogenic balance within the prostate.
An endocrine pathway in the prostate, ERbeta, AR, 5alpha-androstane-3beta,17beta-diol, and CYP7B1, regulates prostate growth.
TLDR
It is suggested that ERbeta, 3betaAdiol, and CYP7B1 are the components of a pathway that regulates growth of the rodent ventral prostate.
An endocrine pathway in the prostate, ERβ, AR, 5α-androstane-3β,17β-diol, and CYP7B1, regulates prostate growth
TLDR
It is suggested that ERβ, 3βAdiol, and CYP7B1 are the components of a pathway that regulates growth of the rodent ventral prostate.
Epimerase activity of the human 11β-hydroxysteroid dehydrogenase type 1 on 7-hydroxylated C19-steroids
Amelioration of Glucose Intolerance by the Synthetic Androstene HE3286: Link to Inflammatory Pathways
TLDR
It is suggested that HE3286 improves glucose homeostasis in diabetic and insulin-resistant mice and suggest that the observed therapeutic effects result from attenuation of proinflammatory pathways, independent of classic sex steroid receptors, corticosteroid receptors, or PPARs.
Comparison of chlordimeform and carbaryl using a functional observational battery.
Progesterone and testosterone hydroxylation by cytochromes P450 2C19, 2C9, and 3A4 in human liver microsomes.
TLDR
The results suggest that CYP2C19 plays important roles in the oxidation of progesterone and testosterone in human liver microsomes, although the physiological significance of these metabolic pathways remains unclear.
Human 3α-hydroxysteroid dehydrogenase isoforms (AKR1C1–AKR1C4) of the aldo-keto reductase superfamily: functional plasticity and tissue distribution reveals roles in the inactivation and formation of male and female sex hormones
TLDR
The kinetic parameters, steroid substrate specificity and identities of reaction products were determined for four homogeneous recombinant human 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) isoforms of the aldo-keto reductase (AKR) superfamily and the functional plasticity of these isoforms highlights their ability to modulate the levels of active androgens, oestrogens and progestins.
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