Wanda W.-S. Chan

A Novel Non-Peptidyl Growth Hormone Secretagogue

Direct screening of preselected compounds in a rat primary pituitary cell culture assay, followed by chemical modification of selected pharmacophores led to the identification of a novel non-peptidyl class of GH secretagogues (substituted benzolactams). The prototype compound of this class, L-692,429, stimulated GH release from rat primary pituitary cells in a time- and dose-dependent manner with an EC50 value of 60 nM. Under the same conditions, His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 (GH-releasing peptide, GHRP-6) and GH-releasing factor (GRF) had EC50 values of 10(-8) and 5 x 10(-10) M, respectively. L-692,428, the S-enantiomer, of L-692,429, was inactive at a concentration as high as 2 microM. GH release induced by L-692,429 was inhibited by somatostatin as well as by GHRP-6 and substance P antagonists but not by GRF or opiate antagonists. L-692,400, which is structurally related to L-692,429 but biologically inactive, inhibited GH response not only to L-692,429 but also GHRP-6. Like GHRP-6, L-692,429 alone had no effect on intracellular cAMP levels; however, it synergized with GRF to further increase both the accumulation of cAMP and the release of GH. Maximal effects of L-692,429 and GHRP-6 on GH release were comparable. Interestingly, when presented together in maximal concentrations, L-692,429 and GHRP-6 did not cause an additional GH release when compared with either secretagogue alone. L-692,429 had a small effect on prolactin release but not adrenocorticotropin.(ABSTRACT TRUNCATED AT 250 WORDS)

Potent 3-spiropiperidine growth hormone secretagogues

Systematic SAR studies of the different regioisomers and homologues of the spiro(indane-1,4-piperidine) moiety in the growth hormone secretagogue L-162,752 are presented. Among them, spiro(3H-1-benzopyran-2,3-piperidine) was found to afford secretagogues with low nanomolar in vitro activity.

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 biological activities of phenyl piperazine-based peptidomimetic growth hormone secretagogues.

A new class of potent, orally active phenyl piperazine-based GH secretagogues have been discovered from attempts to mimic the arrangement of the phenyl substituent in the spiroindanyl piperidine and spiroindoline sulfonamide privileged structures of 4 and 1, respectively. The best of these compounds, 18 (EC50 = 2.8 nM) is nearly as potent as MK-0677 for releasing GH from rat pituitary cells.

Synthesis and biological activities of spiroheterocyclic growth hormone secretagogues

The synthesis and biological activities of a series of spiroheterocyclic growth hormone secretagogues are reported. Modification of the spiroindane part-structure of the prototypal secretagogue L-162,752 revealed that the spiroindane could be replaced with spirobenzodihydrothiophen derivatives to enhance not only in vitro potency but also oral activity. In this study non-aromatic D-2-amino-4-cyclohexylbutanoic analogs (8a-8d) were also identified to be active secretagogues.

Analogs of the orally active growth hormone secretagogue L-162,752

Abstract A series of spiroindane growth hormone secretagogues that vary in their amino side chains is reported. Variations in these side chains markedly affect growth hormone release in vitro and in vivo . The best side chain in this series of secretagogues is α-methylalanine. L-162,752 not only stimulated GH release from rat pituitary cells, but also induced GH release in dogs upon i.v. and p.o. administration.

Synthesis and biological activities of camphor-based non-peptide growth hormone secretagogues

Abstract The synthesis and growth hormone (GH) releasing activities of a novel series of camphor-based non-peptide GH secretagogues is presented. Use of the (R)-nipecotic acid amino side-chain and N-terminal derivatization of it with an (R)-(2-hydroxy)propyl group provided a potent secretagogue 18 (EC 50 = 90 nM). An o -tolyl piperazine was identified as a good replacement for the spiroindanyl piperidine.

Peptidomimetic growth hormone secretagogues: synthesis and biological activities of analogs varied at the indole nucleus of the prototypical spiropiperidine L-162,752

Abstract SAR studies around the indole nucleus of the prototypical peptidomimetic L-162,752 revealed that the D-Trp could be replaced with 3-phenylpropyl-D-glycine and O-benzyl-D-serine to provide secretagogues with comparable intrinsic activity but with significantly better oral activity in dogs. Use of dimethyl β-alanine amino side-chains led to a considerable loss of activity in the D-homophenylalanine and O-benzyl-D-serine series.

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.

Modeling directed design and biological evaluation of quinazolinones as non-peptidic growth hormone secretagogues

Quinazolinone derivatives were synthesized and evaluated as non-peptidic growth hormone secretagogues. Modeling guided design of quinazolinone compound 21 led to a potency enhancement of greater than 200-fold compared to human growth hormone secretagogue affinity of a screening lead 4.