Development of agonistic LHRH analogs

Abstract

The varied and important potential clinical applications ofLHRH stimulated active analog synthesis programs by several groups following the disclosure of its primary sequence (Matsuo et al., 1971a; Burgus et al., 1972). These efforts were directed at an understanding of the structural characteristics of the molecule required for action and at the synthesis of analogs with increased potency and prolonged action. This historical review outlines the development of the synthesis programs which have produced the highly potent LHRH agonistic analogs now under clinical development. Other detailed reviews are available (Schally et al., 1981; Corbin, 1982). STRUCTURE/ACTIVITY RELATIONSHIPS Following the initial descriptions of the synthesis of LHRH (Matsuo et al., 1971b; Monahan et al., 1971), the first analog exhibiting a biological potency greater than LHRH itself ('superagonist') was reported (Fujino et aI., 1972). A study of numerous C-terminal amides of LHRH showed that, while decapeptide amides (e.g. LHRH-methylamide, LHRH-ethylamide, etc.) were only weakly active, nona peptide alkyl amides were very potent. One of these analogs, [Pro 9-NHEt ]LHRH, was six times more potent than LHRH. It was important that the chain length be similar to that of LHRH since longer (NHBu) or shorter (NHMe) analogs were less potent than the NHEt analog. Although 15 different linear and cyclic amines were investigated as C-terminal nonapeptide amides, the ethylamide was the most potent and has appeared frequently in further analogs. The replacement of the other Gly residue in LHRH by o-amino acids yielded superagonist analogs. [o-Ala 6 ]LHRH has a potency five times that of LHRH in a dispersed pituitary cell assay, while the corresponding L-analog, [L-Ala 6 ]LHRH, has only 4 % of the activity ofLHRH (Monahan et al., 1973). The increased potency of the o-isomer was suggested to be due to its ability to stabilize the active conformation of the molecule, since a o-amino acid can stabilize a type IIp-bend when it is in position i + 1 in the turn (Nemethy and 3 B. H. Vickery et al. (eds.), LHRH and Its Analogs