The development of safer GnRH antagonists: strategy and status

Abstract

A milestone in the development of GnRH antagonists h as been reached. Nal-Glu, with reduced histamine-releasing properties relative to Nal-Arg or detirelix (two potent GnRH antagonists which did not survive short-term clinical testing because of observed histamine-related systemic side effects), is now undergoing long-term (16-20 week daily sc administration with testosterone emanthate supplementation) clinical evaluation in males to test the concept that a GnRH antagonist has the potential to be a male contraceptive agent. Short-term daily injections of up to 10 mg of Nal-Glu in male subjects revealed local reactions at the injection site but no systemic toxicity or generalized reactions have been reported (W. Bremner, S. Pavlou, R. Swerdloff). A 90-day toxicology study (K. Sundaram) of Nal-Glu in rats and rabbits revealed no systemic toxicological effects at doses up to 1250 mg/kg , albeit Nal-Glu caused local irritation and inflammatory changes at the injection site. Concurrently, other GnRH antagonists with lesser histamine-releasing properties relative to Nal-Glu have been developed. Thus, whereas Nal-Arg caused severe edema in rats at 1.25 mg/kg and had an ED50=0.17 mg/ml in releasing histamine in an in vitro rat mast cell assay, Nal-Glu exhibited mile edema in rats 12.5 mg/kg and had an ED50=2.0 mg/ml, while Nal-Lys (or antide), soon to undergo phase I single injection clinical studies, showed no edema in rats at 12.5 mg/kg and had an ED50 > 300 mg/ml. Other in vivo histamine-related studies (A. Phillips) support the contention that antide possessed a greater safety margin than Nal-Arg and Nal-Glu. Other GnRH antagonists with reduced histamine-releasing properties are being reported and/or being further developed by various groups. Since the discovery of the histamine-related problems with GnRH antagonists, energy has been directed towards designing antagonists with greatly reduced histamine-releasing properties while maintaining the high gonadotropin suppressive potency of the Nal-Arg generation of antagonists, and these efforts are reviewed in detail. However, attempts are still being made to further increase the potency of the GnRH antagonists and progress towards this new goal will be examined. Structure-activity relationships are discussed in detail and a summary of issues related to the safety of GnRH antagonists is presented.