Identification, synthesis, and biological evaluation of novel pyrazoles as low molecular weight luteinizing hormone receptor agonists.
In the course of a high throughput screening, a series of pyrazole compounds were identified with luteinizing hormone receptor (LH-R) agonist activity. A focused pyrazole library was produced by solid-phase synthesis and key pyrazole regioisomers were obtained selectively in solution. Evaluation of those compounds in a cAMP assay in CHO cells transfected with h-LH receptor allowed us to propose a structure-activity relationship model for this series and led to the identification of the first low molecular weight molecule with in vitro activity in a Leydig cells assay (ED(50)=1.31 microM) and in vivo in a model of testosterone induction in rats (significant effect at 32 mpk ip).
Jorand-Lebrun
Catherine
C
Merck Serono Geneva Research Center, Bat. B3, 9, chemin des Mines, 1211 Geneva, Switzerland. catherine.jorandlebrun@merckserono.net
Brondyk
Bill
B
Lin
Jing
J
Magar
Sharad
S
Murray
Robert
R
Reddy
Adulla
A
Shroff
Hitesh
H
Wands
Greg
G
Weiser
Weishui
W
Xu
Qihong
Q
McKenna
Sean
S
Brugger
Nadia
N
D000818:Animals; D016466:CHO Cells; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D007985:Leydig Cells / Q000378:metabolism; D008297:Male; D008968:Molecular Conformation; D008970:Molecular Weight; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D011974:Receptors, LH / Q000819:agonists*; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000737:chemistry / Q000378:metabolism
D011720:Pyrazoles; D011974:Receptors, LH; D013739:Testosterone