Discovery of a Potent and Short-Acting Oral Calcilytic with a Pulsatile Secretion of Parathyroid Hormone

摘要

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 identifed aminopropandiol 1, which transiently stimulated endogenous PTH secretion in rats. However, the inhibition of cyto- chrome 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 modifcations led to the discovery of the highly potent biphenylcarboxylic acid 15, with a markedly reduced CYP2D6 inhibition and a signi- fcantly 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 profle and agreed well with that of the exogenous PTH injection which exerts a bone anabolic efect.