Background:

AG 045572, also called CMPD1, is a nonpeptidic antagonist of gonadotropin-releasing hormone (GnRH) [1], with Ki values of 6.0 nM and 2.2nM to human and mouse GnRH receptors, respectively [2].

GnRH is a neuroendocrine decapeptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro- Gly-NH2). It is synthesized in the neurovascular terminals of the hypothalamus and hence secreted directly into the hypophyseal portal blood supply in a pulsatile manner. GnRH selectively binds specific receptors on membranes of anterior pituitary gonadotroph cells to stimulate the synthesis and the release of the gonadotropic hormones [follicle-stimulating hormone (FSH) and luteinizing hormone (LH)]. FSH and LH stimulate gametogenesis and gonadal production of sex steroids, respectively [3].

In 293 cells expressing human GnRH receptors, GnRH concentration-dependently increased the accumulation of total [3H] inositol phosphate. This response to GnRH showed an EC50 value of 0.6 ± 0.15 nM (n = 10) with a Hill coefficient of 0.98 ± 0.05. AG 045572 alone did not produce any change in basal levels of inositol phosphates. But AG 045572 concentration-dependently inhibited the response to GnRH. The mean KB ± S.E. of six similar experiments was 25 ± 0.9 nM for AG 045572 at the human receptor. TRH concentration-dependently stimulate the accumulation of total inositol phosphate in GGH3 cells with an EC50 value of 2.4 ± 0.16. AG 045572 at concentrations up to 10 μM had no appreciable inhibition of the accumulation of inositol phosphate stimulated by TRH [3].

After oral administration with AG 045572 at a single dose of 100mg/kg, the concentration of plasma LH in castrated male rats was completely suppressed up to 8 h. 0.5 h after a single intravenous administration with AG 045572 at 10mg/kg, LH levels were suppressed to almost baseline. But this effect lasted for less than 2 h. AG 045572 at a single intravenous dose of 20 mg/kg also reduced concentrations of testosterone in intact male rats [2]. To intact male rats, administration with AG 045572 at a single dose of 100 mg/kg, maintained the suppression of testosterone in the castrate range for 24 hours [4].

参考文献:
[1].  Barnes MJ, Burschka C, Büttner MW, et al. Silicon Analogues of the Nonpeptidic GnRH Antagonist AG-045572: Syntheses, Crystal Structure Analyses, and Pharmacological Characterization. ChemMedChem, 2011, 6(11): 2070-2080.
[2].  Zhu YF, Chen C, Struthers RS. Nonpeptide gonadotropin releasing hormone antagonists. Annu. Rep. Med. Chem, 2004, 39(99): 110.
[3].  Anderes KL, Luthin DR, Castillo R, et al. Biological characterization of a novel, orally active small molecule gonadotropin-releasing hormone (GnRH) antagonist using castrated and intact rats. Journal of Pharmacology and Experimental Therapeutics, 2003, 305(2): 688-695.
[4].  Herbst KL. Gonadotropin-releasing hormone antagonists. Current opinion in pharmacology, 2003, 3(6): 660-666.