5-[5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl-methyl]-N-(2,4,6-trimethoxyphenyl)-2-furancarboxamide

Product Name5-[5,6,7,8-Tetrahydro-3,5,5,8,8-pentamethyl-2-naphthalenyl-methyl]-N-(2,4,6-trimethoxyphenyl)-2-furancarboxamide
CAS263847-55-8
MFC30H37NO5
MW491.62
EINECS
MOL File263847-55-8.mol

Chemical Properties

storage temp.	Store at RT
solubility	<49.16mg/ml in DMSO; <24.58mg/ml in ethanol
form	solid
color	White

Usage And Synthesis

Uses

AG 045572 is a nonpeptidic GnRH antagonist and has the potential as an oral therapeutic treatement for sex hormone-dependent diseases and infertility.

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 T_1/2, CL and V_ss 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	t_1/2 (h)	CL (L/h/kg)	V_ss (L/kg)	C_max (μM)	T_max (h)	F_p.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 T_1/2, CL and V_ss 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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