N 1 -Arylsulfonyl-N 2 -(1-aryl)ethyl-3-phenylpropane-1,2-diamines as Novel Calcimimetics Acting on the Calcium Sensing Receptor Philippe Dauban, a Sandrine Ferry, b HeÂleÁne Faure, b Martial Ruat b and Robert H. Dodd a, * a Institut de Chimie des Substances Naturelles, Centre National de la Recherche Scienti®que, 91198 Gif-sur-Yvette Cedex, France b Laboratoire de Neurobiologie Cellulaire et Mole Âculaire, Junior Group ATIPE, UPR 9040 du CNRS, 91198 Gif-sur-Yvette Cedex, France Received 17 April 2000; revised 26 June 2000; accepted 30 June 2000 AbstractÐThe synthesis and calcimimetic properties of N 1 -arylsulfonyl-N 2 -(1-aryl)ethyl-3-phenylpropane-1,2-diamines are described. The most active compound of the series (3n, used at 10 mM) produced 9711% of the maximal stimulation of [ 3 H]IP production obtained by 10 mM Ca 2+ in CHO cells expressing the calcium sensing receptor (CaSR). This calcimimetic activity was due to a speci®c interaction of this compound with the CaSR. # 2000 Elsevier Science Ltd. All rights reserved. The extracellular calcium sensing receptor (CaSR) is a G-protein coupled receptor which senses extracellular calcium [Ca 2+ ] e as demonstrated recently by the cloning of its cDNA from various tissues including parathyroid and brain. 1 3 This protein belongs to the heptahelical family of receptors that includes metabotropic glutamate receptors (mGluR) 4 and the g-aminobutyric acid receptor (GABA B -R) 5 as well as certain pheromone and taste receptors. 6,7 At the surface of the parathyroid cell, the CaSR detects and responds to small changes of circulating [Ca 2+ ] e leading to regulation of parathyroid hormone (PTH) secretion. 2,8 Elevated concentrations of [Ca 2+ ] e decrease PTH secretion such that the CaSR provides the essential component of calcium homeostasis in the mammalian organism. In humans, point mutations in the CaSR structure produce modi®cations in [Ca 2+ ] e set point that can result in dramatic physiological eects. 9 11 Expression of CaSR occurs also in other tissues impli- cated in calcium homeostasis including thyroid and kidney, and in brain where its expression has been observed in neurons and oligodendrocytes. 3,12,13 Fibroblasts transfected with cloned rat CaSR have allowed initiation of detailed studies of CaSR pharma- cology and its associated transduction signals. 14 16 CaSR is positively coupled to phospholipases C and A2 and its activity can be evaluated by the accumulation of inositol phosphates, intracellular calcium mobilization and release of arachidonates. Besides calcium, cloned CaSR is activated by magne- sium and other divalent cations, by charged molecules such as spermine, spermidine and aminoglycosides and possibly by b-amyloid peptides. 1,14,15,17,18 Recently, two small, non-cationic organic molecules (NPS 568 and NPS 467, 1 and 2, respectively) were reported to interact with cloned CaSR and to mimic or potentiate the eects of [Ca 2+ ] e . 15,16,19 These compounds, referred to as cal- cimimetics, were shown to increase the concentration of cytoplasmic calcium ([Ca 2+ ] i ) in bovine parathyroid cells and inhibit PTH secretion. In the thyroid, CaSR presumably regulates calcitonin secretion and might be preferentially targetted by NPS 467 compared to para- thyroid CaSR. This selectivity is possibly related to minor biochemical dierences in the core protein, suggesting that tissue-speci®c calcimimetics can be designed. 8 Since these compounds only produce eects in the presence of [Ca 2+ ] e , it has been hypothesized that they interact allosterically with the CaSR to increase its sensitivity to [Ca 2+ ] e . In rats, NPS 568 reduced or eliminated osteitis ®brosa 20 and allowed 20±50% reduction of cell proliferation 0960-894X/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved. PII: S0960-894X(00)00382-6 Bioorganic & Medicinal Chemistry Letters 10 (2000) 2001±2004 *Corresponding author. Tel.: +33-1-69-82-45-04; fax: +33-1-69-07- 72-47; e-mail: robert.dodd@icsn.cnrs-gif.fr