William R. Schoen

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.

Synthesis and reactions of 3-substituted-2-phosphomethyl acrylates

Abstract 3-Substituted-2-phosphomethyl acrylates can be prepared from a variety of phophorous nucleophiles and aliphatic or aromatic aldehydes via a sequential Michael reaction followed by a Wittig-Horner-type olefination.

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.

Structure-activity relationships of the non-peptidyl growth hormone secretagogue L-692,429

Abstract Systematic investigation of the amino acid sidechain of L-692,429, the prototype of a novel class of benzolactam growth hormone (GH) secretagogues, has led to the preparation of L-692,585, a 2(R)-hydroxypropyl amino analog, which is twenty times more potent in vitro than L-692,429. Additional amino modifications reported here further define the structure-activity profile for L-692,429.

Benzolactam growth hormone secretagogues: replacements for the 2′-tetrazole moiety of L-692,429

Abstract A variety of 2′-biphenyl substituents was investigated as replacements for the 2′-tetrazole moiety of the non-peptidyl growth hormone secretagogue L-692,429. The 2′-carboxamide 22 and N-2-hydroxypropyl tetrazoles 7a,b were identified as neutral pharmacophores with similar potency to that of the acidic 2′-tetrazole. N-Alkyl tetrazoles, sulfonamides and N-acyl sulfonamides were generally less potent 2′-replacements.

Heterocyclic analogs of the benzolactam nucleus of the non-peptidic growth hormone secretagogue L-692,429

A series of analogs of the non-peptidic benzolactam growth hormone secretagogue L-692,429 was prepared with heteroatom substitutions at the 5-position of the benzolactam ring. Replacement of the 5-position with sulfur or oxygen resulted in secretagogues of approximate equal potency to L-692,429 in the rat pituitary cell assay. Substitution of the 5-position with a carbonyl group or hydroxyl group and replacement of the benzolactam with the 1,4-benzodiazapin-2-one ring system gave analogs of greatly diminished in vitro activity.

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.

BENZOLACTAM GROWTH HORMONE SECRETAGOGUES : REPLACEMENT OF THE C-3 AMIDE BOND IN L-692,429

Abstract The synthesis and structure-activity relationships of various C-3 amide bond modifications in the novel nonpeptidyl growth hormone secretagogue L-692,429 are described. Several C-3 amide surrogates were prepared and the urea moiety was found to exhibit growth hormone releasing activity similar to that observed with L-692,429.

Aliphatic replacements of the biphenyl moiety of the nonpeptidyl growth hormone secretagogues L-692,429 and L-692,585

Abstract Replacement of the central phenyl ring of the biphenyl moiety in the novel growth hormone (GH) secretagogues L-692,429 and L-692,585 with partially or completely saturated surrogates has been investigated. The cyclohexenyl analogue 37 displayed GH releasing activity comparable to L-692,585, indicating that the aromaticity of this central ring is not critical for bioactivity and that this ring may serve primarily to orient the benzolactam and phenyltetrazole pharmacophores.

Chapter 19. Growth Hormone Secretagogues

Publisher Summary With the evolution of modern recombinant DNA technology, human growth hormone has become more widely available. While secretion of pituitary hormones is a complex process that is influenced by a variety of factors, both hormonal and behavioral, the principal regulator is a corresponding hypothalamic releasing factor or secretagogue. The endogenous secretagogues that modulate the secretory pathways have also provided attractive targets for basic and clinical research. The secretion of growth hormone (GH) from the pituitary gland is controlled by a complex neuroendocrine system that in turn regulates the release of two hypothalamic hormones, growth hormone releasing hormone/factor (GHRH, GRF), and somatostatin. The combined effects of growth hormone releasing factor (GRF) and somatostatin produce a pulsatile pattern of GH release that is characterized by pronounced circadian variation (6). GRF also stimulates adenylate cyclase activity resulting in increased rates of synthesis of GH messenger RNA (mRNA) and activation of L-type calcium channels. Agents that stimulate kinase A or kinase C pathways in somatotrophs or compounds causing membrane depolarization also activate L-type calcium channels resulting in GH release. The discovery of human growth hormone releasing factor (hGRF) in 1982, as the primary hypothalamic hormone responsible for the release of growth hormone from pituitary sornatotrophs, has stimulated intense research on this class of secretagogue. The receptor for hGRF has recently been cloned. The complementary DNA (cDNA) encodes a 423-amino acid receptor that has seven transmembrane spanning domains characteristic of G-protein coupled receptors.