tabimorelin and ipamorelin

Topics: Benzazepines; Clinical Trials, Phase I as Topic; Dipeptides; Drug Design; Dwarfism, Pituitary; Ethylamines; Feeding and Eating Disorders; Ghrelin; Growth Hormone; Humans; Ileus; Indoles; Oligopeptides; Peptide Hormones; Sleep Wake Disorders; Spiro Compounds; Stimulation, Chemical; Tetrazoles

In order to obtain more potent growth hormone secretagogues, a comparison of ipamorelin and NN703 suggested the addition of a polar group at the C-terminus of NN703. A study was conducted using constrained amines for this purpose. Here, substituted 4-piperidinylamino- and 4-dimethylaminopiperidino-substituents were found to give the most active compounds. A replacement of the 4-dimethylaminopiperidino-substituent with 4-hydroxypiperidino resulted in a series of compounds, which showed in vitro activity with EC(50) values in the low nanomolar range, and favourable kinetic properties, such as 40% oral bioavailability. The most promising compound was also tested in a swine in vivo model, resulting in a growth hormone level with a C(max) of over 40 ng mL(-1).

Topics: Animals; Biological Availability; Cells, Cultured; Chromatography, High Pressure Liquid; Dipeptides; Dogs; Dose-Response Relationship, Drug; Half-Life; Hormones; Human Growth Hormone; Hydrogen Bonding; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Methylation; Molecular Conformation; Oligopeptides; Rats; Swine

A series of NN703 analogues with lysine mimetics combined with naphthyl- or biphenylalanine in the core has been prepared and tested in vitro in a rat pituitary cell based assay and subsequently in vivo in pigs in a single dose at 50 nmol/kg. Re-introduction of certain pharmacophores in the C-terminal of NN703, which were originally removed during optimisation for oral bioavailability, led to unexpectedly potent compounds in vitro as well as in vivo.

Topics: Administration, Oral; Animals; Biological Availability; Cells, Cultured; Dipeptides; Growth Hormone; Hormones; Indoles; Oligopeptides; Pituitary Gland; Rats; Receptors, Cell Surface; Receptors, G-Protein-Coupled; Receptors, Ghrelin; Spiro Compounds; Structure-Activity Relationship; Swine

A novel class of growth hormone-releasing compounds with a molecular weight in the range from 500 to 650 has been discovered. The aim of this study was to obtain growth hormone secretagogues with oral bioavailability. By a rational approach we were able to reduce the size of the lead compound ipamorelin (4) and simultaneously to reduce hydrogen-bonding potential by incorporation of backbone isosters while retaining in vivo potency in swine. A rat pituitary assay was used for screening of all compounds and to evaluate which compounds should be tested further for in vivo potency in swine and oral bioavailability, fpo, in dogs. Most of the tested compounds had fpo in the range of 10-55%. In vivo potency in swine after iv dosing is reported, and ED50 was found to be 30 nmol/kg of body weight for the most potent compound.

Topics: Administration, Oral; Animals; Biological Availability; Dogs; Drug Evaluation, Preclinical; Female; Growth Hormone; Hormones; Injections, Intravenous; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Molecular Mimicry; Oligopeptides; Pituitary Gland; Rats; Rats, Sprague-Dawley; Structure-Activity Relationship; Swine