Substituted terphenyl compounds as the first class of low molecular weight allosteric inhibitors of the luteinizing hormone receptor.
The luteinizing hormone (LH) receptor plays an important role in fertility and certain cancers. The endogenous ligands human chorionic gonadotropin (hCG) and LH bind to the large N terminal domain of the receptor. We recently reported on the first radiolabeled low molecular weight (LMW) agonist for this receptor, [(3)H]Org 43553, which was now used to screen for new LMW ligands. We identified a terphenyl derivative that inhibited [(3)H]Org 43553 binding to the receptor, which led us to synthesize a number of derivatives. The most potent compound of this terphenyl series, 24 (LUF5771), was able to increase the dissociation rate of [(3)H]Org 43553 by 3.3-fold (at 10 muM). In a functional assay, the presence of 24 resulted in a 2- to 3-fold lower potency of both Org 43553 and LH. Thus, the compounds presented in this paper are the first LMW ligands that allosterically inhibit the LH receptor.
Heitman
Laura H
LH
Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, RA Leiden, The Netherlands.
Narlawar
Rajeshwar
R
de Vries
Henk
H
Willemsen
Milou N
MN
Wolfram
Dieter
D
Brussee
Johannes
J
Ijzerman
Adriaan P
AP
D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D002219:Carbamates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D006801:Humans; D008024:Ligands; D008970:Molecular Weight; D011743:Pyrimidines / Q000494:pharmacology; D011869:Radioligand Assay; D011974:Receptors, LH / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013730:Terphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
C526583:5-amino-2-methylsulfanyl-4-(3-(2-morpholin-4-ylacetylamino)phenyl)thieno(2,3-d)pyrimidine-6-carboxylic acid tert-butylamide; D002219:Carbamates; D008024:Ligands; D011743:Pyrimidines; D011974:Receptors, LH; D013730:Terphenyl Compounds; D013876:Thiophenes; C540186:cyclopentylcarbamic acid (1,1',2',1'')terphenyl-5'-yl ester