Pharmacological and endocrine characterization of A-198401, an orally active GnRH antagonist, in intact and castrate male rat models

Gonadotropin‐releasing hormone (GnRH) stimulates the synthesis and secretion of the gonadotropins that maintain the reproductive axis in mammals. Efforts have focused on the characterization of novel, nonpeptidic orally active antagonists of the GnRH receptor. An erythromycin A derivative, A‐198401 (11‐deoxy‐11‐[carboxy (3,4‐dichlorophenethyl) amino]‐3‐O‐[4‐(S)‐methyl‐oxazolidin‐2‐one] carbamoyl‐5‐O‐(3′‐N‐desmethyl‐3′‐N‐cyclopropylmethyl) desosaminyl‐6‐O‐methyl‐erythronolide A 11,12‐(cyclic carbamate), showed nanomolar affinity for the human (CHO‐21) and rat GnRH receptors in vitro (pK values 8.7 ± 0.2 and 9.2 ± 0.14, respectively). In a functional in vitro assay, A‐198401 inhibited leuprolide‐induced release of luteinizing hormone (LH) from cultured rat pituitary cells with a pA2 value of 8.8. Intravenous (IV) dosing of A‐198401 in castrate male rats produced a significant dose‐dependent suppression of LH production with an ED80 value of 5.26 mg/kg. Sustained testosterone (T) suppression was observed after IV dosing of A‐198401 in the intact rat, with a 10‐mg/kg‐dose producing 9–24 h suppression. Analysis of the IV and PO data indicate that A‐198401 has a bioavailability of 15%. A‐198401 is a novel nonpeptide GnRH antagonist that produces significant and sustained suppression of LH and T production in animal models when dosed either IV or PO and may provide the basis for a therapeutic GnRH antagonist for the clinical treatment of reproductive hormone‐dependent diseases. Drug Dev. Res. 52:485–491, 2001. © 2001 Wiley‐Liss, Inc.