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 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.
Evers
Britta
B
Lilly Forschung GmbH, Division of Eli Lilly Research Laboratories, Essener Bogen 7, 22419 Hamburg, Germany. Evers_Britta@lilly.com
Ruehter
Gerd
G
Berg
Martina
M
Dodge
Jeffrey A
JA
Hankotius
Dirk
D
Hary
Ulrike
U
Jungheim
Louis N
LN
Mest
Hans-Juergen
HJ
de la Nava
Eva-Maria Martin
EM
Mohr
Michael
M
Muehl
Brian S
BS
Petersen
Soenke
S
Sommer
Birgit
B
Riedel-Herold
Grit
G
Tebbe
Mark J
MJ
Thrasher
Kenneth J
KJ
Voelkers
Silke
S
D000613:Aminobutyrates / Q000737:chemistry*; D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry* / Q000633:toxicity*; D002478:Cells, Cultured; D003432:Cross-Linking Reagents / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry* / Q000494:pharmacology*; D013006:Growth Hormone / Q000378:metabolism*; D008297:Male; D008745:Methylation; D015394:Molecular Structure; D010616:Phenanthrenes / Q000737:chemistry* / Q000633:toxicity*; D010902:Pituitary Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry* / Q000494:pharmacology*
C507110:2,3-dihydroisothiazole; C507116:2,3-dimethoxy-8,9-methylenedioxy-benzo(i)phenanthridine-12-carboxylic acid; D000613:Aminobutyrates; D002264:Carboxylic Acids; D003432:Cross-Linking Reagents; D004151:Dipeptides; D010616:Phenanthrenes; D013844:Thiazoles; D012694:Serine; D013006:Growth Hormone