6,7-dihydroxyisoquinoline-3-carboxylic acids are potent inhibitors on the binding of insulin-like growth factor (IGF) to IGF-binding proteins: optimization of the 1-position benzoyl side chain.
A series of 1-benzoyl isoquinolines, based on compound 1, was synthesized and evaluated for their ability to displace IGF-I from its complex with IGF-binding protein-3. Successful modifications of 1 included the replacement of the 3,4-dihydroxybenzoyl group with a substituted benzyl group. These alternations culminated in the discovery of compounds such as 7o which had excellent in vitro potency (K(i)=9.4 nM) but with one less of the labile catechol functionality of 1.
Zhu
Yun-Fei
YF
Department of Medicinal Chemistry, Neurocrine Biosciences, Inc., 10555 Science Center Drive, San Diego, CA 92121, USA.
Wilcoxen
Keith
K
Gross
Timothy
T
Connors
Patrick
P
Strack
Nathalie
N
Gross
Raymond
R
Huang
Charles Q
CQ
McCarthy
James R
JR
Xie
Qiu
Q
Ling
Nicholas
N
Chen
Chen
C
D001565:Benzoates / Q000737:chemistry* / Q000494:pharmacology*; D001667:Binding, Competitive; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007546:Isoquinolines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D001565:Benzoates; D018972:Insulin-Like Growth Factor Binding Protein 3; D007546:Isoquinolines; D007334:Insulin-Like Growth Factor I