Linear and cyclic analogs of GnRH. An update.

Abstract

While the clinical significance of GnRH agonists is well recognized, the potential use of GnRH antagonists in humans awaits the availability of potent analogs with no untoward side effects. We have designed, synthesized and tested in different rat models, several hundred linear and cyclic analogs (agonists and antagonists) of GnRH. We have identified families of linear analogs with high potency in inhibiting ovulation in the rat. Among these families, some have high histamine releasing activity and others have poor solubility in aqueous buffers above pH 6.0. Furthermore, we have identified using a castrated male rat model, analogs exhibiting short (<12 hr) and long (>72 hr) duration of action at a dose of 50 mg/rat. The basis for such resistance to degradation and elimination is specific. Azaline B (Ac-D2Nal-DCpa-D3Pal-Ser-Aph(Atz)-DAph(Atz)-Leu-ILys-Pro-DAla-NH2) (Aph = 4-amino phenylalanine; Atz - aminotriazolyl) and Acyline (Ac-D2Nal-DCpa-D3Pal-Ser-Aph(Ac)-Leu-ILys-Pro-DAla-NH2) are two very promising analogs for further studies in a clinical setting because they are free of histamine releasing activity, are soluble in aqueous buffers, and are particularly long acting after intravenous administration. In parallel, and in order to gain further information on the sterical requirements of side chains, the different stereoisomers of selected b-methyl-amino acids were introduced throughout most of a GnRH antagonist sequence. Finally, mono- and dicyclic analogs of GnRH with potencies comparable to that of the most potent linear analogs were also obtained. Our approach ot the development of such analogs included the use of NMR and computational techniques as well as that of state of the art synthetic approaches. We intend to use the information derived from these SAR studies to design conformationally similar peptido mimetics.