Synthesis and pharmacological evaluation of dimeric follicle-stimulating hormone receptor antagonists.
A series of homo- and heterodimeric compounds encompassing the follicle-stimulating hormone receptor (FSHR) antagonist (R)-1 and its inactive conformer (S)-1 connected through ethylene glycol spacers of various lengths is described. Evaluation of these compounds reveals that dimeric compounds, with a spacer of sufficient length, bearing two active copies of the antagonist are more potent relative to dimeric compounds in which one of the active pharmacophores is replaced by an inactive conformer. Interestingly, the opposite trend is observed if a short spacer is used, indicating that these compounds may be valuable tools to study FSHR dimerization in greater detail.
Bonger
Kimberly M
KM
Leiden Institute of Chemistry, Department of Bioorganic Synthesis, Gorlaeus Laboratories, Leiden University, PO Box 9502, 2300 RA Leiden, The Netherlands.
Hoogendoorn
Sascha
S
van Koppen
Chris J
CJ
Timmers
Cornelis M
CM
Overkleeft
Herman S
HS
van der Marel
Gijsbert A
GA
D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D008024:Ligands; D015394:Molecular Structure; D011962:Receptors, FSH / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013329:Structure-Activity Relationship
D008024:Ligands; D011962:Receptors, FSH