title: Substituted terphenyl compounds as the first class of low molecular weight allosteric inhibitors of the luteinizing hormone receptor.
abstract: 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.
authors.affiliation: Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Leiden University, RA Leiden, The Netherlands.
authors.forename: Laura H
authors.initials: LH
authors.lastname: Heitman
authors.forename: Rajeshwar
authors.initials: R
authors.lastname: Narlawar
authors.forename: Henk
authors.initials: H
authors.lastname: de Vries
authors.forename: Milou N
authors.initials: MN
authors.lastname: Willemsen
authors.forename: Dieter
authors.initials: D
authors.lastname: Wolfram
authors.forename: Johannes
authors.initials: J
authors.lastname: Brussee
authors.forename: Adriaan P
authors.initials: AP
authors.lastname: Ijzerman
mesh_terms: 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
chemical_list: 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