Judith M. Pisano

Lysosomotropic Agents II. Synthesis and Cytotoxic Action of Lysosomotropic Detergents

Amines whose pK values lie between about 5 and 9 are lysosomotropic because lysosomes are acidic intracellular compartments. If such amines bear long hydrophobic chains, they become detergents upon protonation inside the lysosomes, rupturing the lysosomal membrane and killing the cell. Six types of lysosomotropic amines have been prepared that all behave in the expected manner. They are cytotoxic to all lysosome-bearing cells but not red blood cells, which lack lysosomes. Their mode of action, the effect of alkyl chain length on activity, and the fact that their cytotoxic action appears only above a threshhold intracellular concentration support the belief that they behave as lysosomotropic detergents. Among the potential applications is cancer chemotherapy.

Structure-activity relationships in the amino acid sidechain of L-692,429

Abstract Development of L-692,429, the prototype compound of a novel class of growth hormone (GH) secretagogues1, focused on defining the structure-activity relationships in the amino acid sidechain. Modification of the dimethyl-β-alanine group revealed the basic amine as an essential pharmacophore for GH releasing activity. Evaluation of a variety of amino-substittued derivatives led to the identification of analogs with improved potency.

BENZOLACTAM GROWTH HORMONE SECRETAGOGUES : CARBOXAMIDES AS REPLACEMENTS FOR THE 2'-TETRAZOLE MOIETY OF L-692,429

Abstract A variety of 2′-carboxamides was investigated as replacements for the 2′-tetrazole moiety of L-692,429. Investigation of the structure-activity relationships of the carboxamide series determined that primary and secondary carboxamides are potent growth hormone secretagogues in vitro . L-700,653 ( 11 ) was identified as an orally active GH secretagogue in dogs.

Novel derivatives at the C21 position of the FK-506 macrocycle

Abstract A number of C21 derivatives of FK-506 were prepared and their immunosuppressant properties evaluated in a T-cell proliferation assay. Some of these compounds are surprisingly potent antagonists of FK-506-mediated immunosuppression.

Acyclic structural variants of growth hormone secretagogue L-692,429

Systematic investigation of acyclic analogs of L-692,429, the prototype benzolactam growth hormone secretagogue, has helped to further define the structural requirements for the release of growth hormone from rat pituitary cells for this class of secretagogues.