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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...
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Published in: | ACS medicinal chemistry letters 2011-03, Vol.2 (3), p.238-242 |
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creator | Shinagawa, Yuko Inoue, Teruhiko Katsushima, Takeo Kiguchi, Toshihiro Ikenogami, Taku Ogawa, Naoki Fukuda, Kenji Hirata, Kazuyuki Harada, Kazuhito Takagi, Masaki Nakagawa, Takashi Kimura, Shuichi Matsuo, Yushi Maekawa, Mariko Hayashi, Mikio Soejima, Yuki Takahashi, Mitsuru Shindo, Masanori Hashimoto, Hiromasa |
description | 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. |
doi_str_mv | 10.1021/ml100268k |
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Chem. Lett</addtitle><description>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. 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Chem. Lett</addtitle><date>2011-03-10</date><risdate>2011</risdate><volume>2</volume><issue>3</issue><spage>238</spage><epage>242</epage><pages>238-242</pages><issn>1948-5875</issn><eissn>1948-5875</eissn><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. 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subjects | Letter |
title | Discovery of a Potent and Short−Acting Oral Calcilytic with a Pulsatile Secretion of Parathyroid Hormone |
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