A series of tetralins has been reported as GnRH antagonists. Among them, a potent analog AG-045572 (21) has been studied in detail. AG-045572 inhibits 125I-[des-Gly10, d-Ala6]GnRH ethylamide binding to the membranes from rat pituitary glands with a Ki value of 3.8 nM. When tested with membranes prepared from HEK293 cells expressing mouse or human GnRH receptors, it has Ki values of 2.2 and 6.0 nM, respectively. In castrated male rats AG-045572 completely suppresses plasma LH concentration up to 8 h after oral administration of a single dose at 100 mg/kg. After a single intravenous administration at 10 mg/kg, this compound can suppress LH levels to almost baseline at the 0.5-h time point, but this effect lasts less than 2 h. AG-045572 also reduces testosterone concentrations in intact male rats after a single intravenous dose of 20 mg/kg. These data suggest AG-045572 is an efficacious GnRH antagonist [30]. Interestingly, this compound has varying oral bioavailability in rats depending on their endocrine status (F = 8% in intact male rats, and F = 24% in female and castrated male rats) [31]. Another potent analog from this series is 22 with a guanidine structure at right

side of the molecule [32]. Compound 22 is much more hydrophilic than the highly lipophilic AG-045572. This compound has Ki values of 40 nM at the human GnRH receptor and 520 nM at the rat receptor. The KB value of this compound for inhibition of GnRH-stimulated inositol phosphate hydrolysis is 30 nM. Compound 23, which is apparently designed to address the possible poor cell permeability of guanidine 22, has an aminopyrimidine structure [33]. This compound has high binding affinity for both rat and human GnRH receptors (hGnRH Ki = 9.3 nM, rGnRH Ki = 4.7 nM). In cells expressing recombinant rat GnRH receptors, 23 is a competitive inhibitor of GnRH-stimulated extracellular acidification with a pA2 value of 8.3, which is similar to its pKi (8.3) at the rat pituitary receptor. In castrated male rats, 23 dose-dependently suppresses circulating LH levels when given intravenously (5-20 mg/kg). When administrated in intact male rats, 23 significantly lowers circulating testosterone levels for up to 24 h after a single intra-muscular dose of 20 mg/kg. At this dose, plasma levels of 23 is sustained at > 1 mM for over 10 h, suggesting this compound is fairly stable in rats. 23 is also very selective among > 40 receptor, enzyme and channel targets screened, with the exception of D2 dopamine receptors (160 nM) and sodium channel site 2 (200 nM).

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