Biological Activity
Selective gonadotropin-releasing hormone (GnRH) receptor antagonist (K i values are 2.2, 3.8 and 6.0 nM for mouse, rat and human receptors respectively). Suppresses testosterone and luteinising hormone (LH) levels in vivo .
in vivo
AG-045572 (10 mg/kg (i.v.) or 20 mg/kg (p.o.), one time) give to intact male rats, it showed medium T1/2, CL and Vss but oral bioavailability was low, in female rats the bioavailability was much higher (24%), in castrated male rats the pharmacokinetics was similar to that in female rats[1].
AG-045572 (40 mg/kg, i.m. twice a day for 3 days) pretreated of intact male rats resulted in a change of its pharmacokinetics, the parameters became similar to those in female and castrated male rats[1].
Pharmacokinetic Parameters of AG-045572 in Rats after Administration at 10 mg/kg i.v. and 20 mg/kg p.o.[1]
Pharmacokinetic Analysis[1]
| Animals | t1/2 (h) | CL (L/h/kg) | Vss (L/kg) | Cmax (μM) | Tmax (h) | Fp.o. (%) |
| Male | 1.4 ± 0.1 | 2.2 ± 0.5 | 2.1 ± 0.1 | 0.61 ± 0.21 | 1 | 8 |
| Female | 1.7 ± 0.1 | 1.5 ± 0.1 | 2.7 ± 0.4 | 2.31 ± 0.57 | 1 | 24 |
| Castrated male | 1.7 ± 0.4 | 1.5 ± 0.3 | 3.7 ± 1.5 | 1.98 ± 0.51 | 1 | 23 |
| Pretreated male | 1.9 ± 0.2 | 1.5 ± 0.2 | 2.0 ± 0.6 | 1.89 ± 0.41 | 1 | 27 |
| Animal Model: | Male rats were surgically castrated via scrotal approach under halothane anesthesia and allowed 14 days post-operative recovery prior to study[1] |
| Dosage: | 10 mg/kg, 20 mg/kg; 40 mg/kg |
| Administration: | administered acutely at 10 mg/kg (i.v.) or 20 mg/kg (p.o.), one time; For multiple-dose pretreatment, male rats at 40 mg/kg, i.m. twice a day for 3 days. |
| Result: | Showed medium T1/2, CL and Vss but oral bioavailability was low, in female rats the bioavailability was much higher (24%)
Became similar to those in female and castrated male rats.
|
References
[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.
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