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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.

Comparative modeling methods are described that can be used to construct a three-dimensional model structure of a new protein from knowledge of its sequence and of the experimental structures and sequences of other members of its homology family. The methods are illustrated with the mammalian serine protease family, for which seven experimental structures have been reported in the literature, and the sequences for over 35 different protein members of the family are available. The strategy for modeling these proteins is presented, and criteria are developed for determining and assigning the reliability of the modeled structure. Criteria are described that are specially designed to help detect cases in which it is likely that the local structure diverges significantly from the usual conformation of the family.