The discovery of novel calcium sensing receptor negative allosteric modulators

Calcilytics: Antagonists of the Calcium-Sensing Receptor for the Treatment of Osteoporosis

“…Its only, but essential, role is to modify the overall physicochemical properties of such molecules. Unexpectedly, both diastereomers 3a and 3b showed very poor oral bioavailability in rats (<10%) due to high plasma clearance [45]. Subsequently, it was discovered that oral future science group bioavailability could be strongly improved by replacing the phenoxy template with a benzyloxy moiety (FiguRe 3), an element first used by the Japan Tobacco group [42].…”

“…The design of ronacaleret analogs with improved potency and PK properties was described in a recent Pfizer paper [45]. The ethylene linker of ronacaleret between the aromatic ring and the carboxylic acid was replaced by a bulky and greasy bridged ring system.…”

Allosteric Modulation of Family C G-Protein-Coupled Receptors: from Molecular Insights to Therapeutic Perspectives

“…However, NPS2143 has unfavorable pharmacokinetic properties in vivo (see section V.D). Later on, several HTS and lead optimization programs have yielded a number of negative allosteric CaSR modulators from various chemical classes: compounds relatively closely related to NPS2143 (Gavai et al, 2005), but also different molecules, such as Calhex 231 (compound II in Table 13) and derivatives thereof (Petrel et al, 2003;Kessler et al, 2006), trisubstituted pyridines/ pyrimidines (compound V in Table 13) (Arey et al, 2005;Yang et al, 2009), benzyloxy analogs (compound IV in Table 13) (Balan et al, 2009), 2-benzylpyrrolidinesubstituted aryloxypropanols (compound VI in Table 13) , 3H-quinazolin-4-ones (compound VII in Table 13) (Shcherbakova et al, 2005), and 4-arylquinazolin-2-ones (compound VIII in Table 13) (Widler et al, 2010) were identified as novel calcilytics, having essentially similar effects on intracellular calcium mobilization and inositol formation in cellular assay systems, some of them also being active in vivo. More compounds having in vivo activity are discussed below.…”

The osteocyte as a therapeutic target in the treatment of osteoporosis

“…However, to be useful as anabolic agents, calcilytic agents must induce the release of sufficient PTH to be anabolic, they must have a short half-life since sustained activation would result in prolonged PTH secretion and a catabolic state (hyperparathyroidism), and they should not deplete the parathyroid gland, and not result in hyperplasia [Avlani et al 2013]. Recently, a calcilytic agent, called ronacaleret, has shown a strong PTH response, with a short half-life, and an increase in both cortical and trabecular bone formation in rodents [Balan et al 2009;Atchison et al 2011]. However, a recent clinical trial involving ronacaleret in humans showed a small, nondose-dependent increase in bone-mineral density in the lumbar spine at 6 months [Fitzpatrick et al 2012].…”