title: Novel orally active growth hormone secretagogues.
abstract: 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.
authors.affiliation: Departments of Medicinal Chemistry Research, Assay and Cell Technology, Growth Hormone Pharmacology, and Pharmacokinetics, Health Care Discovery and Preclinical Development, Novo Nordisk A/S, Novo Nordisk Park, DK2760 Målov, Denmark.
authors.forename: T K
authors.initials: TK
authors.lastname: Hansen
authors.forename: M
authors.initials: M
authors.lastname: Ankersen
authors.forename: B S
authors.initials: BS
authors.lastname: Hansen
authors.forename: K
authors.initials: K
authors.lastname: Raun
authors.forename: K K
authors.initials: KK
authors.lastname: Nielsen
authors.forename: J
authors.initials: J
authors.lastname: Lau
authors.forename: B
authors.initials: B
authors.lastname: Peschke
authors.forename: B F
authors.initials: BF
authors.lastname: Lundt
authors.forename: H
authors.initials: H
authors.lastname: Thøgersen
authors.forename: N L
authors.initials: NL
authors.lastname: Johansen
authors.forename: K
authors.initials: K
authors.lastname: Madsen
authors.forename: P H
authors.initials: PH
authors.lastname: Andersen
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004353:Drug Evaluation, Preclinical; D005260:Female; D013006:Growth Hormone / Q000378:metabolism*; D006728:Hormones / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D007275:Injections, Intravenous; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D006728:Hormones; D009842:Oligopeptides; C041048:growth hormone releasing hexapeptide; D013006:Growth Hormone; C114611:ipamorelin