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.

Kv11.1 (hERG)‐induced cardiotoxicity: a molecular insight from a binding kinetics study of prototypical Kv11.1 (hERG) inhibitors

“…LogK W‐C8 values were measured on a Supelcosil LC‐ABZ, 5 cm × 4.6 mm, 5 μm column (Supelco, Bellefonte, PA, USA) according to a methodology described previously (Lombardo et al ., ; Heitman et al ., ). In short, retention times of the compounds were determined at three different methanol percentages.…”

Human TSH receptor ligands as pharmacological probes with potential clinical application

“…They are usually synthesized chemically, can be produced in large quantities at modest cost and can typically be administered orally because they are not degraded within, and can be absorbed from the gastrointestinal (GI) tract. For these reasons, a number of small-molecule agonists [71–75] and an antagonist [76] for LHCGR, and small-molecule agonists [77–83] and antagonists [82,84,85] for FSHR have recently been reported. Development of small-molecule ligands for TSHR has lagged behind those for other glycoprotein hormone receptors.…”

Palladium-Catalyzed Aerobic Dehydrogenation of Substituted Cyclohexanones to Phenols

“…As a representative example, O -terphenylcarbamate 5 was recently identified as a potent in-vitro allosteric inhibitor of the human luteinizing hormone receptor, which has been implicated in fertility and ovarian cancer ( 25 ). This compound was prepared by traditional Suzuki coupling methods using 3,5-dibromophenol as the starting material; however, introduction of the unsymmetrical aryl substitution pattern results in low yields of the biaryl intermediate 6 and the desired 3,5-diarylphenol 4 (30% and 62% yields, respectively; Fig.…”