The human calcium-sensing receptor (CaSR) primarily functions to maintain systemic calcium homeostasis, mainly by suppressing parathyroid hormone secretion. Polymorphisms in the human CaSR have been correlated to diseases of calcium homeostasis such as familial hypocalciuric hypercalcemia. Ma et al. describe the properties of a new CaSR allosteric agonist with different binding properties compared with current calcimimetics (e.g., cinacalcet) used to treat disorders of calcium homeostasis. AC-265347 is a structurally novel benzothiazole human CaSR allosteric agonist that interacts with the transmembrane domain of human CaSR with a binding mode different from that of existing calcimimetics. The structural differences of these benzothiazoles from existing calcimimetics translate into greater activity at CaSRs carrying a variety of artificial and naturally occurring loss-of-function mutations. Unlike cinacalcet, AC-265347 does not inhibit CYP2D6, suggesting a significantly reduced potential for drug-drug interactions. These studies suggest that AC-265347 and its structural analogs have the potential to be developed into effective calcimimetics and may provide therapeutic advantages over cinacalcet in certain patient populations.
See article at J Pharmacol Exp Ther 2011, 337:275–284.
- Copyright © 2011 by The American Society for Pharmacology and Experimental Therapeutics