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

ACS Med Chem Lett. 2010 Dec 29;2(3):238-42. doi: 10.1021/ml100268k.

Yuko Shinagawa ¹, Teruhiko Inoue ¹, Takeo Katsushima ¹, Toshihiro Kiguchi ¹, Taku Ikenogami ¹, Naoki Ogawa ¹, Kenji Fukuda ¹, Kazuyuki Hirata ¹, Kazuhito Harada ¹, Masaki Takagi ¹, Takashi Nakagawa ¹, Shuichi Kimura ¹, Yushi Matsuo ¹, Mariko Maekawa ¹, Mikio Hayashi ¹, Yuki Soejima ¹, Mitsuru Takahashi ¹, Masanori Shindo ¹, Hiromasa Hashimoto ¹

Affiliations

Affiliation

1 Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan.

PMID: 24900301 DOI: 10.1021/ml100268k

Abstract

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.

Keywords

Calcium-sensing receptor (CaSR) antagonist; PTH; calcilytics; cytochrome P450 inhibition; osteoporosis; short-acting.

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