Structure activity studies of the serine-AIB dipeptide domain in 2,3-dihydroisothiazole based growth hormone secretagogues

A series of growth hormone secretagogues (GHSs) based on 2,3-dihydroisothiazole has been synthesized in the search for a potential treatment of growth hormone deficiency or frailty in the elderly. This paper describes the evaluation of the SAR of the benzyl- d-Ser-aminoisobutyric acid dipeptide frag...

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Published in:Bioorganic & medicinal chemistry 2005-12, Vol.13 (24), p.6748-6762
Main Authors: Evers, Britta, Ruehter, Gerd, Berg, Martina, Dodge, Jeffrey A., Hankotius, Dirk, Hary, Ulrike, Jungheim, Louis N., Mest, Hans-Juergen, de la Nava, Eva-Maria Martin, Mohr, Michael, Muehl, Brian S., Petersen, Soenke, Sommer, Birgit, Riedel-Herold, Grit, Tebbe, Mark J., Thrasher, Kenneth J., Voelkers, Silke
Format: Article
Language:English
Subjects:
Aminobutyrates - chemistry
Animals
Biological and medical sciences
Carboxylic Acids - chemistry
Carboxylic Acids - toxicity
Cells, Cultured
Cross-Linking Reagents - chemistry
Dipeptides - chemistry
Dipeptides - pharmacology
Growth hormone
Growth Hormone - secretion
Growth hormone secretagogue
Hormones. Endocrine system
Male
Medical sciences
Methylation
Molecular Structure
Pharmacology. Drug treatments
Phenanthrenes - chemistry
Phenanthrenes - toxicity
Pituitary Gland - cytology
Pituitary Gland - drug effects
Pituitary Gland - secretion
Rats
Rats, Sprague-Dawley
Serine - chemistry
Structure-Activity Relationship
Thiazoles - chemistry
Thiazoles - pharmacology
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Summary:A series of growth hormone secretagogues (GHSs) based on 2,3-dihydroisothiazole has been synthesized in the search for a potential treatment of growth hormone deficiency or frailty in the elderly. This paper describes the evaluation of the SAR of the benzyl- d-Ser-aminoisobutyric acid dipeptide fragment. Introduction of substituents in the peptide backbone and in the phenyl ring has been investigated, as well as replacements for the benzyl group and for the AIB residue. A number of modifications resulted in enhanced potency over the parent benzyl- d-Ser-AIB derivative.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2005.07.070