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

Abstract

The only bone anabolic agents currently available on the market are based on the parathyroid hormone (PTH). Secretion of endogenous PTH is controlled by a calcium-sensing receptor at the surface of the parathyroid glands. Antagonists of this receptor (calcilytics) induce the release of the hormone. Provided the effect of the calcilytic is of short duration, a bone anabolic effect should also result. Although the first calcilytic series became known approximately 10 years ago, the number of different structural types is still small today. This article outlines the quest from hits to potent development candidates of all relevant calcilytic series currently known. Even after the front-runners unexpectedly failed in the clinic, the approach for an oral alternative to parenteral PTH remains highly attractive.

The calcium-sensing receptor in bone metabolism: from bench to bedside and back

“…ATX914 has also been demonstrated to display good pharmacokinetic properties and encouraging results following single-dose administration in healthy human volunteers and postmenopausal women [101]. However, in a phase I study of 4 weeks with 42 postmenopausal women receiving ATX914 orally, no statistically significant increases in bone formation markers were seen, and more importantly, dose-dependent hypercalcemia was observed, causing the termination of the compound [102].…”

GENETICS IN ENDOCRINOLOGY: Gain and loss of function mutations of the calcium-sensing receptor and associated proteins: current treatment concepts

“…NPS-2143 and its close relative ronacaleret are amino-alcohols, whereas ATF936 and AXT914 are quinazolinones. These different classes of calcilytics have partly different bindings sites (48) and data from four publications show that some but not all ADH CASR mutants were sensitive to NPS-2143 (108,111,112,113). In contrast all five ADH and all four BS5 mutants tested so far were sensitive to ATF936 and AXT914 (111).…”

“…In addition, cinacalcet has been used for treatment of hyperparathyroidism related to hereditary vitamin D-resistant rickets (43) and X-linked hypophosphatemia (44). Allosteric CASR inhibitors called calcilytics (45,46,47) are currently investigated as a way to stimulate endogenous PTH secretion for the treatment of osteoporosis (48,49,50) and they have been proposed as a novel therapeutic strategy to treat allergic asthma (51), pulmonary hypertension (52) and Alzheimer's disease (53).…”

Towards a structural understanding of allosteric drugs at the human calcium-sensing receptor

“…Thus, there is an unmet need to develop novel PAMs and NAMs that show enhanced clinical efficacy with reduced adverse effects. Encouragingly, new classes of CaSR modulators have now been disclosed, and more than 10 structurally distinct scaffolds confer PAM or NAM activity [12,13]. Moreover, some of these modulators display unique pharmacology compared to the prototypical modulators.…”