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1-Alkyl-4-phenyl-6-alkoxy-1H-quinazolin-2-ones: A Novel Series of Potent Calcium-Sensing Receptor Antagonists

Widler, Leo, Altmann, Eva, Beerli, Rene, Breitenstein, Werner, Bouhelal, Rochdi, Buhl, Thomas, Gamse, Rainer, Gerspacher, Marc, Halleux, Christine, John, Markus, Lehmann, Hansjoerg, Kalb, Oskar, Kneissel, Michaela, Missbach, Martin, Mueller, Irene, Reidemeister, Sibylle, Taillardat, Agnes, Tommasi, Ruben, Weiler, Sven, Wolf, Romain, Seuwen, Klaus and Renaud, Johanne (2010) 1-Alkyl-4-phenyl-6-alkoxy-1H-quinazolin-2-ones: A Novel Series of Potent Calcium-Sensing Receptor Antagonists. Journal of Medicinal Chemistry, 53 (5). pp. 2250-2263. ISSN 0022-2623


Parathyroid hormone (PTH) is an effective bone anabolic agent. However, only when administered by daily s.c. injections exposure of short duration results, a pre-requisite for an anabolic response. Instead of applying exogenous PTH, mobilization of endogenous stores of the hormone can be envisaged. The secretion of PTH stored in the parathyroid glands is mediated by a calcium sensing receptor (CaSR) a GPCR localized at the cell surface. Antagonists of CaSR (calcilytics) mimic a state of hypocalcaemia and stimulate PTH release to the blood stream.
The starting point for the Novartis calcilytics project was the proprietary structure 2a found by screening of the internal compound collection for inhibition of CaSR signaling function using a fluorimetric assay for intracellular calcium (FLIPR). The compound had an IC50 of 1.5 M and was an interesting starting point for lead optimization being a close analogue of Proquazone, an analgesic developed by Sandoz in the 1980s.
Optimization of the series resulted in an increase in in vitro potency by a factor of >100. Key to potency improvement of 2a was the replacement of the 6-methoxy substituent by an propargyloxy moiety (7h). The part of the structure most tolerant to changes was the N(1) substituent. Compounds 10 with N-benzyl groups and especially the thio-analog 11k were among the most potent derivatives. The binding mode of our compounds was predicted based on molecular modeling and confirmed by testing with mutated receptors.
While the compounds readily induced PTH release after i.v. application special formulation was needed for oral activity. The required profile was achieved by using micro-emulsions. Excellent PK/PD correlation was found in rats and dogs. High levels of PTH were reached in plasma within minutes which revert to baseline in about 1-2 hours in both species.

Item Type: Article
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Additional Information: Archiving not formally supported by this publisher
Keywords: Calcilytic; Calcium sensing receptor antagonist; PTH release
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Date Deposited: 13 Oct 2015 13:16
Last Modified: 13 Oct 2015 13:16


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