PHYSICOCHEMICAL PROPERTIES OF A-75998, AN ANTAGONIST OF LUTEINIZING-HORMONE-RELEASING HORMONE

The physicochemical properties of A-75998, a synthetic antagonist of l uteinizing hormone releasing hormone with potential for treatment of h ormone-sensitive cancers and endometriosis, are described. An accelera ted solution stability study indicated that the compound is relatively stable and showed a U-shaped pH-rate profile, with maximum stability between pH 4.5 and 6.5. The acid dissociation behavior of A-75998 was examined by UV-visible spectrophotometry at 25 degrees C in a series o f buffers ranging from pH 1 to 13. The data were fit to a model in whi ch the dissociations of all four ionizable groups contributed to chang es in the absorbance. The estimated macroscopic acid dissociation cons tants were p beta(1) = 3.230 +/- 0.022, p beta(2) = 4.885 +/- 0.030, p beta(3) = 9.871 +/- 0.022, and p beta(4) = 11.026 +/- 0.157. The corr esponding microscopic dissociation constants were pk(1) = 3.24 (nicoti nyl), pk(2) = 4.88 (pyridyl), pk(5) = 9.91 (tyrosyl), and pk(6) = 10.9 9 (isopropyllysyl). The apparent n-octanol/water partition coefficient s were measured from pH 2 to 13, and the profile was consistent with t he expected acid-dissociation behavior. While appearing fairly water-s oluble at pH < 5, dynamic light scattering of A-75998 in pH 4.5 buffer indicated the formation of aggregates of nonuniform size distribution . A-75998 exhibited reverse or thermal gelation; sodium chloride exace rbates this gel formation and self-association. Surface activity was p H-dependent, but no evidence was found for micelle formation. Based on the results, development of a parenteral formulation of A-75998 appea rs feasible, provided that aggregation can be minimized.