New potent calcimimetics: II. Discovery of benzothiazole trisubstituted ureas

Following the identification of trisubstituted ureas as a promising new chemical series of allosteric modulators of the calcium sensing receptor (CaSR), we further explored the SAR around the urea substitution, leading to the discovery of benzothiazole urea compound 13. This compound is a potent cal...

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Veröffentlicht in:	Bioorganic & medicinal chemistry letters 2013-04, Vol.23 (8), p.2455-2459
Hauptverfasser:	Deprez, Pierre, Temal, Taoues, Jary, Hélène, Auberval, Marielle, Lively, Sarah, Guédin, Denis, Vevert, Jean-Paul
Format:	Artikel
Sprache:	eng
Schlagworte:	Benzothiazole urea Benzothiazoles - chemical synthesis Benzothiazoles - chemistry Benzothiazoles - pharmacology Calcium - chemistry Calcium sensing receptor Positive allosteric modulators Receptors, Calcium-Sensing - antagonists & inhibitors Urea - analogs & derivatives Urea - chemical synthesis Urea - chemistry Urea - pharmacology
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Zusammenfassung:	Following the identification of trisubstituted ureas as a promising new chemical series of allosteric modulators of the calcium sensing receptor (CaSR), we further explored the SAR around the urea substitution, leading to the discovery of benzothiazole urea compound 13. This compound is a potent calcimimetic with an EC50=20nM (luciferase assay). Evaluated in an in vivo model of chronic renal failure (short term and long term in 5/6 nephrectomized rats), benzothiazole urea 13 significantly decreased PTH levels after oral administration while keeping calcemia within the normal range.
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2013.01.077