Teruhiko Inoue

Discovery of a potent and short-acting oral calcilytic with a pulsatile secretion of parathyroid hormone.

Short-acting oral calcilytics, calcium-sensing receptor (CaSR) antagonists, have been considered as alternatives for parathyroid hormone (PTH), an injectable bone anabolic drug used in the treatment of osteoporosis. Previously, we identified aminopropandiol 1, which transiently stimulated endogenous PTH secretion in rats. However, the inhibition of cytochrome P450 (CYP) 2D6 and the low bioavailability of 1 remain to be solved. Attempts to change the physicochemical properties of the highly lipophilic amine 1 by introduction of a carboxylic acid group as well as further structural modifications led to the discovery of the highly potent biphenylcarboxylic acid 15, with a markedly reduced CYP2D6 inhibition and a significantly improved bioavailability. Compound 15 evoked a rapid and transient elevation of endogenous PTH levels in rats after oral administration in a dose-dependent manner at a dose as low as 1 mg/kg. The PTH secretion pattern correlated with the pharmacokinetic profile and agreed well with that of the exogenous PTH injection which exerts a bone anabolic effect.

New aminopropandiol derivatives as orally available and short-acting calcium-sensing receptor antagonists

Synthesis and structure-activity relationship studies on a new aminopropandiol class of derivatives as calcium-sensing receptor antagonists are described. Modification of the phenolic moiety of a calcilytic compound NPS 2143 led to the identification of an orally available compound (R,R)-31 which demonstrated a rapid and transient stimulation of PTH release in rats.